U.S. patent number 6,355,669 [Application Number 09/529,675] was granted by the patent office on 2002-03-12 for retinoic acid agonists as preventive and therapeutic agents for nephritis.
This patent grant is currently assigned to Eisai Co., Ltd.. Invention is credited to Akira Ishibashi, Mitsuo Nagai, Naoki Tokuhara, Toshihiko Yamauchi.
United States Patent |
6,355,669 |
Yamauchi , et al. |
March 12, 2002 |
Retinoic acid agonists as preventive and therapeutic agents for
nephritis
Abstract
The present invention provides a therapeutic or prophylactic
agent as a substitute for conventional steroids or
immunosuppressive agents to treat or prevent systemic
erythematosus, glomerulonephritis, lupus nephritis, idiopathic
thrombocytopenic purpura or autoimmune anemia. The agent comprises
a retinoic acid receptor agonist, specifically a retinoic acid
receptor subtype .alpha. (RAR.alpha.) agonist, including for
example: (1) carboxylic acid compounds having condensed rings
represented by the following formula: ##STR1## (wherein the rings L
and M are condensed, are the same as or different from each other,
and represent an aromatic hydrocarbon which may have a substituent
group or a heterocycle which may have a substituent group; the
rings A and B are independent of each other and represent an
aromatic hydrocarbon ring or heterocycle which may have a
substituent group; and D represents a carboxyl group which may have
a protective group), (2)
4-{[(3,5-bistrimethylsilylphenyl)carbonyl]amino}benzoic acid,
4-{2-[5-(3-methoxymethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene
-2-yl)pyrrolyl]}benzoic acid, etc.
Inventors: |
Yamauchi; Toshihiko (Tsukuba,
JP), Ishibashi; Akira (Tsukuba, JP),
Tokuhara; Naoki (Tsukuba, JP), Nagai; Mitsuo
(Tsukuba, JP) |
Assignee: |
Eisai Co., Ltd. (Tokyo,
JP)
|
Family
ID: |
17751450 |
Appl.
No.: |
09/529,675 |
Filed: |
April 18, 2000 |
PCT
Filed: |
September 22, 1998 |
PCT No.: |
PCT/JP98/04266 |
371
Date: |
April 18, 2000 |
102(e)
Date: |
April 18, 2000 |
PCT
Pub. No.: |
WO99/20309 |
PCT
Pub. Date: |
April 29, 1999 |
Foreign Application Priority Data
|
|
|
|
|
Oct 22, 1997 [JP] |
|
|
9-290073 |
|
Current U.S.
Class: |
514/427; 514/429;
514/469; 548/517; 548/529; 549/469; 549/491 |
Current CPC
Class: |
A61K
31/00 (20130101); A61K 31/40 (20130101); A61K
31/4025 (20130101); A61K 31/4155 (20130101); A61K
31/498 (20130101); A61K 31/55 (20130101); A61K
31/695 (20130101) |
Current International
Class: |
A61K
31/695 (20060101); A61K 31/00 (20060101); A61K
31/40 (20060101); A61K 31/4155 (20060101); A61K
31/4025 (20060101); A61K 31/55 (20060101); A61K
31/498 (20060101); A61K 031/40 (); A61K 031/34 ();
C07D 405/00 (); C07D 307/78 () |
Field of
Search: |
;514/427,429,469
;548/517,529 ;549/469,491 |
References Cited
[Referenced By]
U.S. Patent Documents
|
|
|
5081271 |
January 1992 |
Koichi et al. |
6121309 |
September 2000 |
Tagami et al. |
|
Foreign Patent Documents
|
|
|
|
|
|
|
838453 |
|
Apr 1998 |
|
EP |
|
889032 |
|
Jan 1999 |
|
EP |
|
1-249783 |
|
Oct 1989 |
|
JP |
|
WO94/17796 |
|
Aug 1994 |
|
WO |
|
WO9702244 |
|
Jan 1997 |
|
WO |
|
9702244 |
|
Jan 1997 |
|
WO |
|
WO97/24116 |
|
Jul 1997 |
|
WO |
|
9315740 |
|
Sep 1997 |
|
WO |
|
9734869 |
|
Sep 1997 |
|
WO |
|
Other References
Elder James T. et al.;"Retinoid induction of . . . human dermal . .
. " J.Inv.Der.106/3, 517-21,Mar. 1996.* .
Germuth, Immunopathology of the Renal Glomerulus pp 181-194. .
Mangelsdorf The Retinoid Receptors 2nd ed. 1994, pp 319-349. .
Brinckerhoff, Science 221, 756-758, 1983 Inflammation and
Collagenase Production in Rats etc. .
Racke J. Immunol. 154, 450-458 Retinoid Treatment of Experimental
Allergic Encephalomyelitis. .
Apfel Proc. Natl. Acad. Sci. 89 7129-7133 A retinoic acid Receptor
.alpha. antagonist selectively etc. .
Blomhoff J. Biol. Chem., 25 23988-23992, 1992 Vitamin A is a Key
Regulator for Cell Growth etc. .
Fahlman J. Immunol. 155 58-65, 1995 All-trans- and 9-cis-Retinoic
Acid Inhibit Growth of Normal etc. .
Kuwabara FEBS Letters 378 153-156, 1996 Novel Synthetic retinoic
acid inhibits rat collagen etc. .
Lomo J. Cell. Physiol. 175 68-77 1998 RAR-, not RXR, Ligands
Inhibit Cell Activation and Prevent etc. .
Buck J. Cell Biol. 115 851-859 1991 Differences in the Action and
Metabolism between Retinol etc..
|
Primary Examiner: Raymond; Richard L.
Assistant Examiner: Patel; Sudhaker B.
Attorney, Agent or Firm: Nixon & Vanderhye
Parent Case Text
This application is a 35 U.S.C. .sctn.371 of PCT/JP98/04266, filed
Sep. 22, 1998.
Claims
What is claimed is:
1. A method of treating nephritis or lupus nephritis comprising
administering to a subject in need of same an effective a compound
of the following formula or a pharmacologically acceptable salt
thereof or a hydrate of the salt: ##STR32##
where R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.8 each
represents hydrogen, halogeno, optionally substituted lower alkyl,
optionally substituted cycloalkyl, optionally substituted aryl,
optionally substituted heteroaryl, optionally substituted lower
alkoxy, optionally substituted aryloxy, optionally substituted
heteroaryloxy, optionally substituted cycloalkylalkyl, optionally
substituted arylalkyl, optionally substituted heteroarylalkyl,
optionally substituted cycloalkyloxy, optionally substituted
cycloalkylalkyloxy, optionally substituted arylalkyloxy, optionally
substituted heteroarylalkyloxy, optionally substituted alkenyl or
optionally substituted alkynyl, or alternatively two of R.sup.1,
R.sup.2, R.sup.3, R.sup.4 and R.sup.8 adjacent to each other
together with the carbon atoms to which they are bonded
respectively may form a ring which may contain a heteroatom or be
substituted; A represents an optionally substituted pyrrole ring, B
represents an optionally substituted aromatic hydrocarbon ring or
an optionally substituted unsaturated heterocycle; and D represents
an optionally protected carboxyl.
2. The method as claimed in claim 1, wherein B represents an
optionally substituted phenyl group or pyridyl group.
3. The method of claim 1, wherein the compound is selected from the
group consisting of
4-{2-[5-(4,7-dimethylbenzofuran-2-yl)pyrrolyl]}benzoic acid;
4-{2-[5-(7-fluoro-4-trifluoromethylbenzofuran-2-yl)pyrrolyl]}benzoic
acid;
4-{2-[5-(3-fluoro-4,7-dimethylbenzofuran-2-yl)pyrrolyl]}benzoic
acid; and
4-{2-[5-(7-ethyl-4-methylbenzofuran-2-yl)pyrrolyl]}benzoic
acid.
4. The method as claimed in claim 1, wherein nephritis is
treated.
5. The method as claimed in claim 1, wherein lupus nephritis is
treated.
6. A method of claim 1, wherein the compound is ##STR33##
7. A method of treating nephritis or lupus nephritis comprising
administering to a subject in need of same an effective amount of a
compound selected from the group consisting of
4-{2-[5-(4,7-dimethylbenzofuran-2-yl)pyrrolyl]}benzoic acid;
4-{2-[5-(7-fluoro-4-trifluoromethylbenzofuran-2-yl)pyrrolyl]}benzoic
acid;
4-{2-[5-(3-fluoro-4,7-dimethylbenzofuran-2-yl)pyrrolyl]}benzoic
acid; and
4-{2-[5-(7-ethyl-4-methylbenzofuran-2-yl)pyrrolyl]}benzoic acid.
Description
FIELD OF THE INVENTION
The present invention relates to a therapeutic or prophylactic
agent for glomerulonephritis, lupus nephritis, idiopathic
thrombocytopenic purpura or autoimmune anemia, which comprises a
retinoic acid receptor (RAR) agonist as an active ingredient. In
particular, the present invention relates to a therapeutic or
prophylactic agent for systemic erythematosus, glomerulonephritis,
lupus nephritis, idiopathic thrombocytopenic purpura or autoimmune
anemia, which comprises a retinoic acid receptor subtype .alpha.
(RAR.alpha.) agonist as an active ingredient.
PRIOR ART
1) Glomerulonephritis
Glomerulonephritis is generally called nephritis where continuous
albuminuria and hematuria are clinically observed, and shows a
morbid state in which renal functional disturbance and
complications of edema, high blood pressure and cardiac
insufficiency due to storage of sodium occur in some cases.
Pathogenically, glomerulonephritis can be defined as a glomerular
disease showing an increase in mesangium (phonetic transcription)
cells and/or substrate in renal glomeruli.
The most universal idea on the mechanism of the onset of
glomerulonephritis is that immune reaction products occurring on
glomeruli damage the glomeruli. It is also evident from the fact
that the damage is caused by heteroantibody and host antibody in an
animal experiment. Masugi experimentally created glomerulonephritis
by intravenously administering duck-derived nephrotoxic serum
against rabbit renal tissues into normal domestic rabbits, and
domestic rabbit-derived nephrotoxic serum against rat renal tissues
into rats, thus demonstrating that glomerulonephritis is generated
by an immunological mechanism (Masugi, M., Beitr. Pathol. Anat.,
91, 82-112, 1933, Masugi, M., Beitr. Pathol. Anat., 92, 429-466,
1934). Since fluorescent antibody techniques were introduced for
renal materials in biopsy in the 1960's, there have been reported a
large number of data suggesting that an immunological mechanism is
involved in generating glomerulonephritis in humans as well. In
nephritis caused by these immune reactions, sedimentation of an
antigen-antibody immune complex (IC) onto glomeruli is particularly
important.
From the previous results of studies on animal experiment models,
nephritis caused by precipitation of IC in circulating blood and
nephritis by formation of IC in situ are being considered. The
former is nephritis caused by binding a protein antigen originally
unrelated to glomerular tissues to its corresponding antibody in
blood, to form IC which is then precipitated on a glomerular sling
wall or on mesangium. The latter includes 2 types of nephritis: one
is caused by IC formed by binding an antibody against a renal
tissue antigen (unique component in glomerular basement membrane
and glomerular cells) directly to glomeruli, and the other is
caused by IC formed by precipitation of an extraneous antigen via
electrical charge or other affinity on glomeruli and subsequent
binding of its corresponding antibody to the glomeruli in situ. The
site on which IC is precipitated includes mesangium observed in
endothelial cells and IgA nephropathy, in addition to epithelial
cells observed in human nephropathy originating in membrane. The
factors determining the precipitation site include the size of
immune complex, the electric charge of antigen, antibody and immune
complex, the binding force between antigen and antibody, and type
and subclass of antibody. These factors are involved in
precipitating an immune complex in blood or forming an immune
complex in situ followed by activation of complements to initiate
inflammation reaction.
Major therapeutic agents used at present for glomerulus nephritis
include anti-platelet agents, anti-coagulating agents,
adrenocortical steroids and immunosuppressive agents. Among these,
as described above, the immunological mechanism is involved
considerably in the onset of nephritis so that conventional therapy
for nephritis is based on adrenocortical steroids inhibiting immune
response.
The nephrosis syndrome is a disease to which adrenocorticotrophic
steroids are most suited. However, the glomerulus nephritis as a
causative disease for the nephrosis syndrome has various types
ranging from the primary to secondary one, thus revealing that
thereactivity of steroids to the nephritis syndrome is varied
depending on the type of nephritis. For example, the complete
remission of minimal change nephrotic syndrome (MCNS) is achieved
in 80 to 95% cases by steroids. However, the effect of therapy with
steroid is hardly expected except for only the case of IgA
nephropathy where the degree of albuminuria is moderate while renal
function is maintained, and in only this case, the therapy with
steroid is performed. About 2/3 of patients with acute nest-like
glomerular sclerosis respond to steroids, but the other 1/3
patients are resistant to steroids and advance to terminal-stage
renal insufficiency, and patients with chronic glomerular sclerosis
are also hardly responsive to steroids. Although a reduction in
albuminuria in nephropathy originating in membrane
(glomerulonephritis originating in membrane) is recognized by use
of steroids for aprolonged period of time, stringent evaluation of
this therapy is still not be established. Further, secondary lupus
nephritis is classified into I to IV types in renal biopsy, and the
clinical effect of the steroids thereon is varied; the effect on
the IV type (diffuse proliferation type) cannot be expected even by
administering in a large amount, rather there is the possibility of
aggravation.
An immunosuppressive agent is used in combination when therapy
using only adrenocortical steroid is insufficient in the case of
steroid-resistant and frequently relapsing nephrosis syndrome,
rapidly progressive glomerulonephritis or lupus nephritis, or for
the purpose of reducing the dose of the adrenocortical steroid.
Generally used agents include cyclophosphamide, cyclosporin A and
mizoribine. Cyclophosphamide is used frequently, but there occur
various side effects depending on the dose. Major side effects
include bone marrow inhibition, hepatic damage, alopecia, lung
fibrosis, bleeding cystitis and hypofunction of sexual glands.
Cyclosporin A shows an immunosuppressive action on T cells, but it
has severe side effects include renal damage, hepatic damage,
central nerve damage, infections and acute pancreatitis, among
which the renal damage occurs depending on the blood concentration,
thus making it necessary to monitor the blood concentration.
Mizoribine has less side effects than other immunosuppressive
agents, but is poor in effect on the diseases.
As described above, there are a large number of cases where the
effects of the adrenocortical steroids used as the first choice in
conventional therapy are not satisfactory, while the
immunosuppressive agents used for compensating therefor have the
problem of side effects.
2) Autoimmune Diseases in which Autoantibody is Involved
The autoantibody observed in autoimmune diseases is roughly divided
into 2 groups depending on the characteristic distribution of its
corresponding antigen in the body. The first group is an
organ-specific autoantibody observed in organ-specific autoimmune
diseases. This kind of autoantibody corresponds to
anti-thyroid-stimulating hormone receptor antibody detected in
patients with Basedow's disease, or to an anti-acetyl choline
receptor antibody detected in patients with severe myasthenia. The
second group is the one which reacts with antigen present in almost
all organs in the body or in serum, and is called organ-unspecific
autoantibody. The characteristic autoantibody in systematic
autoimmune diseases such as glycogen storage disease is included in
this group. These autoimmune antibodies directly damage organs or
form an immune complex thereby generating the morbid state of
autoimmune diseases. Further, even in autoimmune diseases wherein
the relationship between the presence of autoantibody and the
morbid state is not clear, the detection of autoantibody is
revealed to be clinically important as being indicative of
diagnosis, activity of the diseases, and judgement of therapeutic
effect. Hereinafter, some typical autoimmune diseases in which
autoantibody is involved are described.
Systemic lupus erythematosus (SLE) shows various symptoms, and
symptoms and examination views adopted as classification criteria
includes the following 11 items: 1) cheek erythema, 2) disk-shaped
erythema, 3) hypersensitivity to light, 4) ulcer in the oral
cavity, 5) arthritis, 6) serositis, 7) renal damage, 8) nerve
damage, 9) blood abnormality, 10) immune abnormality, and 11)
antinuclear antibody. These symptoms and abnormalities in
examination are considered due to autoantibody. It is estimated
that antinuclear antibody as typical autoantibody forms an immune
complex and causes disturbance such as lupus nephritis via the III
type allergy mechanism. Lupus nephritis is observed in 60% of
patients with systematic erythematosus, and for the treatment,
adrenocortical steroids are used. However, in the case of
steroid-resistant lupus nephritis or when there occur severe side
effects of steroids, administration of an immunosuppressive agent
is taken into consideration. An immunosuppressive agent used
frequently is azathiopurine or cyclophosphamide.
Idiopathic thrombocytopenic purpura (ITP) is a disease in which
autoantibody against platelets is produced to destroy platelets.
Clinical symptoms include the tendency of bleeding caused by a
reduction in platelets, and bleeding occurs mainly under the skin
and on the mucosa to cause purpura, petechia and blood spot. When
platelets are significantly reduced, there occur complications of
oral bleeding, nasal bleeding, genital bleeding, bloody excrements,
retinal hemorrhage etc., and the most severe case, the
complications are accompanied by cranial hemorrhage. For general
treatment of ITP, an adrenocortical steroid is used as a first
choice, followed by conducting pancreatectomy. However, there are
not few cases showing resistance to this standard treatment, and in
these cases, treatment by administration of an immunosuppressive
agent or danazole is attempted, but the effectiveness is not so
high.
In autoimmune hemolytic anemia, antibody against self-erythrocytes
is produced to cause hemolysis, and anemia and jaundice are
clinically observed. Treatment is based on administration of
steroids, and an immunosuppressive agent is also used if response
is poor, or to reduce maintenance dose of steroids. However, it was
recognized that about 1/4 of the patients are worsened during
maintenance therapy.
In Basedow's disease, autoantibody against thyroid-stimulating
hormone receptors stimulates the thyroid to cause hyperthyroidism.
As clinical symptoms, diffuse struma, tachycardia, tremor of
fingers are observed. For treatment, the inhibition of formation of
the hormone by administering an anti-thyroid drug such as
thiamazole or propyl thiouracil, by destruction of the thyroid
gland with radioactive iodine, or by subtotal resection of the
thyroid gland by operation is performed, but there is no
established therapeutic method against the causative factor of the
disease.
Accordingly, the object of the present invention is to provide a
therapeutic or prophylactic agent as a substitute for conventional
steroids or immunosuppressive agents to treat systemic
erythematosus, glomerulonephritis, lupus nephritis, idiopathic
thrombocytopenic purpura or autoimmune anemia.
Retinoic acid plays an important role for growth of animal and in
maintaining functions, such as specific regulation of
differentiation and proliferation of cells and morphological
formation of vertebrates. In connection with these physiological
actions, retinoic acid attracts attention as an anticancer agent or
as a specific remedy for proliferated skin diseases (psoriasis and
keratosis), and a number of retinoic acid analogues have been
synthesized. In recent years, the presence of .alpha., .beta. and
.gamma. subtypes of retinoic acid receptor was revealed (The
Retinoids, 2nd ed., Raven Press, Ltd., New York, 1994, Sporn, M.
B., Roberts, A. B., Goodman, D. S.). However, the physiological
importance of each receptor has not been revealed yet.
On the other hand, the intimate involvement of vitamin A in the
immune system has been known from of old. There are many reports in
which retinoic acid as a product of metabolism of vitamin A acts
for inhibition of the immune system. For example, Brinckerhoff et
al. have reported that secondary inflammations in rat adjuvant
arthritis as a model with human rheumatic arthritis are
significantly suppressed by administering 13-cis-retinoic acid
(Brinckerhoff, C. E., et al., Science 221, 756, 1983). Further,
Racke et al. have reported that neural symptoms of mouse allergic
cerebrospinal meningitis as a model with human multiple sclerosis
is ameliorated by administering retinoids such as 13-cis-retinoic
acid and 4-hydroxyretinamide (Racke, M. K., et al., J. Immunol.,
154, 450-458, 1995). It is suggested that in these models,
retinoids ameliorate the morbid state by inhibiting the activation
of T-lymphocytes.
In addition, it is also reported that retinoids inhibit the
activation of B lymphocytes. That is, it is reported that
all-trans-retinoic acid inhibits polyclonal division of mouse B
lymphocytes or human B lymphocytes (Apfel, C., Proc. Natl. Acad.
Sci. USA, 89, 7129-7133, 1992, Blomhoff, H. K., et al., J. Biol.
Chem., 25, 23988-23992, 1992 and Fahlman, C., et al., J. Immunol.,
155, 58-65, 1995). Further, it is reported that Am80 which is a
retinoic acid receptor subtype .alpha. (RAR.alpha.) agonist
strongly inhibited production of anti-collagen antibody titer in
blood in a rat model with collagen arthritis (Kuwabara, K., et al.,
FEBS Letters, 378, 153-156, 1996).
It is shown that retinoids act on B lymphocyte via retinoic acid
receptor (RAR) (Blomhoff, H. K., et al., J. Cell. Physiol., 175,
68-77, 1998). Further, it is suggested that RAR.alpha. has an
important role in demonstrating the actions described above, from
the following findings: (1) among RAR subtypes, RAR.alpha. and
RAR.gamma. are expressed in human B lymphocytes, and in particular
RAR.alpha. is strongly expressed, while RAR.beta. is not expressed
(Blomhoff, H. K., et al. 1998, supra, and Buck, J. L., et al., J.
Cell. Biol., 115, 851-859, 1991) and (2) the inhibitory action of
retinoic acid on differentiation of mouse B lymphocytes was
recovered almost perfectly by adding RAR.alpha. antagonist (Ro
41-5253) (Apfel, C., 1992, supra).
As described above, retinoids inhibit the activation of B
lymphocytes in addition to T lymphocytes, and this effect is
suggested to be via RAR.alpha. in particular among the RAR
subtypes. However, even the reports mentioned above do not contain
any description indicating a clear relationship between RAR or
RAR.alpha. and production of antibody by B lymphocytes.
WO94/17796, U.S. Pat. No. 4,703,110, JP-A 2-76862, JP-A 63-255277,
JP-A 8-505359, WO97/24116 etc. disclose the use of retinoid-like
active compounds for treating a wide variety of inflammatory,
allergic and rheumatic immune diseases including cancers such as
leukemia, breast cancer, prostate cancer, lung cancer, esophagus
and respiratory tract cancer, skin cancer and bladder cancer; skin
diseases such as psoriasis, keratosis, eczema, atopic dermatitis,
acne and Darier's disease; autoimmune diseases such as chronic
articular rheumatism and erythematosus; chronic polyarthritis,
spinal arthritis and deformable arthritis. However, these
publications neither suggest a therapeutic method against specific
causative factors, for example by utilizing the inhibitory action
of RAR agonist on production of autoantibody to treat autoimmune
diseases in which the autoantibody is involved, nor contain any
description of glomerulonephritis, lupus nephritis, idiopathic
thrombocytopenic purpura and autoimmune anemia. However, in only
WO97/34869 there appears a description of glomerulonephritis, but
there is no disclosure on specific data suggesting or clearly
showing the effect, nor is there a description of lupus nephritis,
idiopathic thrombocytopenic purpura and autoimmune anemia. Further,
there is none of the description that among RAR agonists, subtype
.alpha.-agonist contributes particularly to prevention and
treatment of systematic erythematosus and glomerulus nephritis.
DISCLOSURE OF THE INVENTION
The present inventors extensively studied retinoid compounds and
found that RAR agonists have potent inhibitory action on production
of antibody. On the basis of this finding, they further continued
the study to find that among a plurality of subtype receptors,
particularly RAR.alpha. agonist acting on .alpha.-receptor is a
major agonist contributing to the inhibitory action, thus
completing the present invention.
The present invention relates to a therapeutic or prophylactic
agent for a disease against which the inhibitory action of a
retinoic acid receptor (RAR) agonist or a pharmacologically
acceptable salt thereof as an active ingredient on production of
antibody is effective. Further, the present invention relates to
use of a retinoic acid receptor (RAR) agonist or a
pharmacologically acceptable salt thereof for producing a
therapeutic or prophylactic agent for a disease against which the
inhibitory action thereof on production of antibody is
effective.
That is, the present invention relates to a therapeutic or
prophylactic agent for systematic erythematosus,
glomerulonephritis, lupus nephritis, idiopathic thrombocytopenic
purpura or autoimmune anemia, wherein a retinoic acid receptor
(RAR) agonist, particularly an RAR.alpha. agonist or a
pharmacologically acceptable salt thereof, comprising compounds
shown (1) to (12) below, is used as an active ingredient.
1) carboxylic acid compounds having condensed rings represented by
the formula (I): ##STR2##
wherein the rings L and M are condensed, are the same as or
different from each other and represent an aromatic hydrocarbon
which may have a substituent group or a heterocycle which may have
a substituent group, the rings A and B are independent of each
other and represent an aromatic hydrocarbon ring or heterocycle
which may have a substituent group, and D is a carboxyl group which
may have a protective group,
2) carboxylic acid compounds having heterocycle disclosed in JP-A
9-71566, which are represented by the formula (II): ##STR3##
wherein A represents the following groups: ##STR4##
(wherein R.sup.1 to R.sup.3, R.sup.18 to R.sup.28 and R.sup.30 to
R.sup.36 are the same as or different from and represent hydrogen
atom, a halogen atom, a lower alkyl group or a phenyl group which
may have a substituent group, and the formula ---------- represents
a single or double bond),
B represents a heteroarylene group which may have a substituent
group, an arylene group which may have a substituent group, the
group represented by the formula --CONH-- or the group represented
by the formula --CR.sup.6.dbd.CR.sup.7 -- (wherein R.sup.6 and
R.sup.7 are the same as or different from each other and represent
hydrogen atom, a lower alkyl group or a halogen atom),
D represents an arylene group which may have a substituent group, a
heteroarylene group which may have a substituent group or the group
represented by the formula --CR.sup.6.dbd.CR.sup.7 (wherein R.sup.6
and R.sup.7 have the same meanings as defined above), n.sub.1 is 0
or 1, and
M represents hydroxyl group, a lower alkoxy group or the group
represented by the formula --NR.sup.16 R.sup.17 (wherein R.sup.16
and R.sup.17 are the same as or different from each other and
represent hydrogen atom, hydroxyl group, a lower alkyl group, a
hydroxyalkyl group, an aryl group or a heteroaryl group, or
R.sup.16 and R.sup.17 may, together with a nitrogen atom to which
they are bound, form a ring optionally containing an oxygen or
sulfur atom,
3)
4-{2-[5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl)pyrrolyl]}
benzoic acid,
4-{2-[5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl)franyl]}be
nzoic acid,
4-{2-[5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl)thiophenyl
]}benzoic acid or
4-{2-[5-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl)pyrazolyl]
}benzoic acid disclosed in JP-A 2-240058,
4) 4-[2-(3,4-dihydro-2H-1-benzopyran-6 or 7-yl)propenyl]benzoic
acid compounds, 4-[2-(3,4-dihydro-2H-1-benzothiopyran-6 or
7-yl)propenyl]benzoic acid compounds,
4-[2-(1,2,3,4-tetrahydroquinoline-6 or 7-yl)propenyl]benzoic acid
compounds, 4-{[(3,4-dihydro-2H-1-benzopyran-6 or
7-yl)carbonyl]amino}benzoic acid compounds,
4-{[(3,4-dihydro-2H-1-benzothiopyran-6 or
7-yl)carbonyl]amino}benzoic acid compounds or
4-{[(1,2,3,4-tetrahydroquinoline-6 or 7-yl)carbonyl]amino}benzoic
acid compounds disclosed in JP-A 2-76862,
5) 4-(trimethylsilyl-substituted phenyl)benzoic acid compounds
disclosed in JP-A 1-249783,
6) [(3,4-dihydro-2H-1-benzopyran-6-yl)ethynyl]heteroaryl carboxylic
acid compounds,
[(3,4-dihydro-2H-1-benzothiopyran-6-yl)ethynyl]heteroaryl
carboxylic acid compounds or
[(1,2,3,4-tetrahydroquinoline-6-yl)ethynyl]heteroaryl carboxylic
acid compounds disclosed in JP-A 63-255277,
7)
(E)-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenol
compounds disclosed in JP-A 62-267245,
8)
4-{[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]amino}benz
oic acid compounds disclosed in JP-A 61-22047,
9) 9-(substituted phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraene-1-one
acid compounds disclosed in JP-A 49-126637,
10) all-trans-retinoic acid,
11)
4-{2-[5-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalene-2-yl)pyrrolyl
]}benzoic acid or
4-{2-[5-(3-methoxymethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene
-2-yl)pyrrolyl]}benzoic acid, and
12)
4-{[(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl)carbonyl]amino
}benzoic acid compounds,
4-{[(2,2,4,4-tetramethylchroman-2-yl)carbonyl]amino}benzoic acid
compounds or 4-{[(2,6-di-t-butylpyrido-4-yl)carbonyl]amino}benzoic
acid compounds disclosed in WO97/24116.
In the present invention, preferable compounds include:
all-trans-retinoic acid;
4-{[(3,5-bistrimethylsilylphenyl)carbonyl]amino}benzoic acid
compounds disclosed in JP-A 1-249783;
4-{[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]amino}benz
oic acid or
4-{[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)amino]carbonyl}benz
oic acid disclosed in JP-A 61-22047; and the compound group
represented by the following general formula: ##STR5##
wherein L, M, A, B and D have the same meanings as defined above,
##STR6##
wherein A, B, D, M and n.sub.1 have the same meanings as defined
above.
More preferable compounds are the compound group shown in (1) to
(20) below:
(1) 4-{2-[5-(5,8-dimethylnaphthalene-2-yl)pyrrolyl]}benzoic acid,
(2) 4-{2-[5-(8-methylnaphthalene-2-yl)pyrrolyl]}benzoic acid, (3)
4-{2-[5-(8-ethylnaphthalene-2-yl)pyrrolyl]}benzoic acid, (4)
4-{2-[5-(8-isopropylnaphthalene-2-yl)pyrrolyl]}benzoic acid, (5)
4-{2-[5-(8-isopropenylnaphthalene-2-yl)pyrrolyl]}benzoic acid, (6)
4-{2-[5-(8-penylnaphthalene-2-yl)pyrrolyl]}benzoic acid, (7)
4-{2-[5-(4,7-dimethylbenzofuran-2-yl)pyrrolyl]}benzoic acid, (8)
4-{2-[5-(4,7-dichlorobenzofuran-2-yl)pyrrolyl]}benzoic acid, (9)
4-{2-[5-(5-chloro-7-ethylbenzofuran-2-yl)pyrrolyl]}benzoic acid,
(10) 4-{2-[5-(4,7-dimethylbenzothiophene-2-yl)pyrrolyl]}benzoic
acid, (11)
4-{2-[5-(3-fluoro-4,7-dimethylbenzofuran-2-yl)pyrrolyl]}benzoic
acid, (12)
4-{2-[5-(7-ethyl-4-methylbenzofuran-2-yl)pyrrolyl]}benzoic acid,
(13)
4-{2-[5-(7-fluoro-4-trifluoromethylbenzofuran-2-yl)pyrrolyl]}benzoic
acid, (14)
4-{2-{5-[3-(1-ethyl-5-isopropylpyrazolyl)]pyrrolyl}}benzoic acid,
(15)
4-{2-{5-[7-(1,5-dimethyl-2,3,4,5-tetrahydro-1H-benzazepinyl}pyrrolyl}benzo
ic acid, (16)
4-{4-{2-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylquinoxalynyl)]furyl}}ben
zoic acid, (17)
4-{2-{5-[2-(8,8-dimethyl-5,6,7,8-tetrahydroquinoxalynyl)]pyrrolyl}}benzoic
acid, (18)
4-{[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)amino]carbonyl}
benzoic acid, (19)
4-{[(3,5-bistrimethylsilylphenyl)carbonyl]amino}benzoic acid and
(20)
4-{2-[5-(3-methoxymethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene
-2-yl)pyrrolyl]}benzoic acid.
In the present invention, the term "may have a substituent group"
means that the group may be substituted by the group selected from
hydroxyl group; thiol group; nitro group; cyano group; halogen atom
such as fluorine atom, chlorine atom, bromine atom and iodine atom;
lower alkyl group such as methyl, ethyl, n-propyl and isopropyl;
lower alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy
and butoxy group; halogenated alkyl group such as fluoromethyl
group, difluoromethyl group, trifluoromethyl group and
2,2,2-trifluoroethyl group; alkylthio group such as methylthio
group, ethylthio group and isopropylthio group; acyl group such as
acetyl group, propionyl group and benzoyl group; hydroxyalkyl group
such as hydroxymethyl group, hydroxyethyl group and hydroxypropyl
group; amino group; monoalkyl amino group such as methyl amino
group, ethyl amino group and isopropyl amino group; dialkyl amino
group such as dimethyl amino group and diethyl amino group;
carboxyl group; alkoxy carbonyl group such as methoxy carbonyl
group, ethoxy carbonyl group and propyl carbonyl group; carbamoyl
group; alkyl carbamoyl group such as methyl carbamoyl group and
dimethyl carbamoyl group; acyl amino group such as acetyl amino
group and benzoyl amino group; alkyl sulfonyl group such as
sulfamoyl group, methyl sulfonyl group and ethyl sulfonyl group;
unsubstituted or substituted aryl sulfonyl group such as benzene
sulfonyl group and p-toluene sulfonyl group; unsubstituted or
substituted aryl group such as phenyl group, tolyl group and
anisolyl group; unsubstituted or substituted heteroaryl group such
as pyrrole group, pyrazolyl group, imidazolyl group, triazolyl
group, tetrazolyl group, thiazolyl group, pyridyl group, pyrimidyl
group and pyrazinyl group; carboxy alkyl group; alkyloxycarbonyl
alkyl group such as methoxycarbonyl methyl group, ethoxycarbonyl
methyl group and methoxycarbonyl ethyl group; carboxyalkoxy group
such as carboxymethoxy group; aryl alkyl group such as benzyl group
and 4-chlorobenzyl group; heteroaryl alkyl group such as pyridyl
methyl group and pyridyl ethyl group; and alkylene dioxy group such
as methylene dioxy group and ethylene dioxy group.
The aromatic hydrocarbon means benzene, naphthalene, anthracene
etc.
The heterocycle means a group derived from a monocyclic ring
containing 1 to 3 atoms of at least one member selected from the
group consisting of sulfur atom, oxygen atom and nitrogen atom. For
example, it means a pyrrole ring, thiophene ring, furan ring,
thiazole ring, oxazole ring, isothiazole ring, isoxazole ring,
imidazole ring, pyrazole ring, thiadiazole ring, oxadiazole ring,
triazole ring, pyridine ring, pyridazine ring, pyrimidine ring,
pyrazine ring etc.
The halogen atom means a fluorine atom, chlorine atom and iodine
atom.
The lower alkyl group means a C.sub.1 to C.sub.6 linear or branched
alkyl group such as methyl group, ethyl group, n-propyl group,
n-butyl group, isopropyl group, isobutyl group and n-hexyl
group.
The arylene group means the above aromatic hydrocarbon group having
two bonds available for bonding.
The heteroarylene group means the above heterocyclic group having
two bonds available for bonding.
The compound of formula (I) can be obtained easily by an ordinarily
used method or a combination of ordinarily used methods. One
example is as follows:
The compound wherein ring A is a pyrrole ring can be obtained in
the following method. ##STR7##
(Step 1)
In this reaction, the aldehyde (1) is reacted in a usual manner
with an organometallic reagent to give the allyl alcohol (2).
The organometallic reagent includes e.g. a Grignard reagent, an
organic lithium reagent, an organic zinc reagent and an organic
copper complex. In the presence of a catalytic amount of copper
iodide, the desired product can be produced in higher yield. The
reaction solvent maybe any solvents which is inert to the reaction,
and preferable examples include ether solvents such as ether and
tetrahydrofuran. The reaction temperature is in the range of about
-78.degree. C. to the boiling point of the solvent, and preferably
about -78.degree. C. to 20.degree. C.
(Step 2)
In this step, the allyl alcohol (2) obtained in step 1 is oxidized
in a conventional manner to give the vinyl ketone (3).
The oxidation may be conducted in any ordinarily used methods,
preferably using a suitable oxidizing agent. The examples of
oxidizing agent used include activated manganese dioxide,
chlorochromate pyridium, dichromate pyridium, a Dess-Martin
reagent, a Swern oxidizing agent, TEMPO (sodium
2,2,6,6-tetramethyl-1-piperidinyloxy hypochlorite)-copper chloride,
TEMPO-NaOCl etc. The reaction solvent may be any solvents which is
inert to the reaction, and preferable examples include
dichloromethane, chloroform, acetone etc. The reaction temperature
is in the range of about -78.degree. C. to the boiling point of the
solvent, and preferably about -78.degree. C. to 20.degree. C.
(Step 3)
In this step, the diketone compound shown in the formula (5) is
obtained by the method of Stetter 5 described in Org. Synth. 65, 26
by use of the vinyl ketone (3) obtained in step 2 and the aldehyde
(4).
In this reaction, use of a thiazolium salt catalyst brings
preferable results. For this reaction, a base such as triethylamine
and sodium acetate is preferably used. A reaction solvent such as
methanol, ethanol, N,N-dimethylformamide, etc. is used. The
reaction temperature is preferably about 60.degree. C. to the
boiling point of the solvent.
(Step 4)
In this step, the diketone (5) obtained in step 3 is treated in a
usual manner to give the pyrrole compound represented by the
formula (6).
For example, by the reaction with an ammonium salt such as ammonium
acetate or with a primary amine, the desired compound (6) can be
obtained. In this case, an alcohol solvent such as methanol and
ethanol, acetic acid or the like is used as the reaction solvent.
The reaction temperature is preferably about 70.degree. C. to the
boiling point of the solvent.
The pyrrole (6) obtained in step 4 is hydrolyzed in a usual manner
whereby its corresponding carboxylic acid compound can be obtained.
In this case, use of a base brings good results. As the base, an
aqueous solution of lithium hydroxide, sodium hydroxide, potassium
hydroxide or the like gives rise to good results. The reaction
solvent is preferably alcohol solvent such as methanol and ethanol
or ether solvent such as tetrahydrofuran. The reaction temperature
is preferably about 20.degree. C. to the boiling point of the
solvent.
Processes for producing the other compound group are disclosed in
JP-A 9-71566, JP-A 2-240058, JP-A 2-768.62, JP-A 1-249783, JP-A
63-255277, JP-A 61-22047, and WO97/24116.
The compounds of the present invention are administered orally or
parenterally. The compound group of the present invention can be
administered in forms such as tablets, powder, granulates,
capsules, syrups, troches, suppositories, injections, intravenous
drip infusions, ointments, nasal drops, poultices and lotions.
The dose varies depending on the severeness of symptoms, the age,
sex, weight and sensitivity of the patient, the administration
method, administration time, administration intervals, the
properties of the pharmaceutical preparation used, and its active
ingredient, and there is no particular limit to the dose. Usually,
the daily dose for an adult is 0.1 to 2000 mg, preferably 0.1 to
1000 mg. Usually this daily dose is administered in one portion or
in divided portions. When administered in the form of an injection,
usually 1 to 1000 .mu.g/kg, preferably 1 to 300 .mu.g/kg is
administered.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows the effect of compounds A, B, C and D on production of
anti-rabbit .gamma.-globulin (RGG) antibody in rats.
FIG. 2 shows the effect of compounds B, E, F, G and H on production
of anti-dinitrophenyl (DNP) antibody in mice.
FIG. 3 shows the effect of etretinate on production of
anti-dinitrophenyl (DNP) antibody in mice.
FIG. 4 shows the effect of compounds A, B and D on production of
anti-DNA antibody in (NZB.times.NZW) F1 mice.
EXAMPLES
Hereinafter, the effects of the compounds of the present invention
on nephritis and autoimmune diseases in which autoantibody is
involved are described more in detail by reference to Examples.
In the test compounds used in the following experiment, compound A
is 4-{2-[5-(4,7-dimethylbenzofuran-2-yl)pyrrolyl]}benzoic acid,
compound B is
4-{2-[5-(7-fluoro-4-trifluoromethylbenzofuran-2-yl)pyrrolyl]}benzoic
acid, compound C is
4-{2-[5-(3-fluoro-4,7-dimethylbenzofuran-2-yl)pyrrolyl]}benzoic
acid, compound D is
4-{2-[5-(7-ethyl-4-methylbenzofuran-2-yl)pyrrolyl]}benzoic acid,
compound E is
4-{2-{5-[2-(8,8-dimethyl-5,6,7,8-tetrahydroquinoxalynyl)]pyrrolyl}}benzoic
acid, compound F is
4-{2-{5-[7-(1,5-dimethyl-2,3,4,5-tetrahydro-1H-benzazepinyl)]pyrrolyl}}ben
zoic acid, compound G is
4-{2-{5-[3-(1-ethyl-5-isopropylpyrazolyl]pyrrolyl}}benzoic acid,
compound H is
4-{2-[5-(3-methoxymethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene
-2-yl)pyrrolyl}}benzoic acid, and compound I is
4-{[(3,5-bistrimethylsilylphenyl)carbonyl]amino}benzoic acid.
Example 1
A Rat Model with Accelerated Nephritis
Sprague-Dawley strain rats were immunized by subcutaneously
administering rabbit .gamma.-globulin in a dose of 4 mg/rat along
with Freund's complete adjuvant into the bottoms of their both hind
legs. On the 5th day after the rats were immunized, 1 ml of
anti-rat glomerular basement membrane rabbit serum diluted 6- or
8-fold was administered via tail veins into the animals. On the 8th
day, the rats were forced to be orally administered 8 ml sterilized
water and then placed in a metabolism cage, and their urine was
collected for 24 hours during which the animals were allowed
neither food nor water. As the indicator of the model with
accelerated Masugi nephritis, the amount of proteins excreted in
urine for 24 hours was used.
The test compounds A, B, C, D, E, F, H and I were suspended
respectively in 0.5% aqueous methyl cellulose solution and orally
administered into the rats once every day from the day on which the
animals were immunized with rabbit .gamma.-globulin to the day
before urine was collected from the animals. The medium was
administered into the control group.
The results are shown in Table 1. Compounds A, B, C, D and H, in a
dose of 0.3 mg/kg, inhibited albuminuria by 60 to 90% or more as
compared with the control group. Further, compounds E, F and I, in
a dose of 1 mg/kg, inhibited albuminuria by 70 to 80% or more as
compared with the control group.
TABLE 1 Effect of Compounds A, B, C, D, E, F, H and I on the model
with Accelerated Masugi Nephritis Degree of Inhibition Dose Number
of of Albuminuria Test Compound (mg/kg) Animals (%) Compound A 0.3
5 69.2 Compound B 0.3 5 90.7 Compound C 0.3 5 87.7 Compound D 0.3 5
80.3 Compound E 1.0 7 85.8 Compound F 1.0 7 71.1 Compound H 0.3 7
61.3 Compound I 1.0 7 89.4
Example 2
A Rat Model Producing Antibody
Sprague-Dawley strain rats were immunized by subcutaneously
administering rabbit .gamma.-globulin in a dose of 4 mg/rat along
with Freund's complete adjuvant into the bottoms of their both hind
legs. On the 14th day after the rats were immunized, blood was
collected from their tail veins and examined for anti-rabbit
.gamma.-globulin antibody titer in serum by the ELISA method.
The test compounds A, B, C and D were suspended respectively in
0.5% aqueous methyl cellulose solution and orally administered once
every day for 14 days from the day on which the animals were
immunized with rabbit .gamma.-globulin. The medium was administered
into the control group.
The results are shown in Table 1.
Compounds B, C and D inhibited significantly in a dose of 0.3 mg/kg
the anti-rabbit .gamma.-globulin IgG2a antibody titer on the 14th
day after immunization. Compound A showed a tendency to inhibit the
antibody titer in a dose of 0.3 mg/kg.
Example 3
A Mouse Model Producing Antibody
BALB/c mice were immunized by administering dinitrophenylated
keyhole limpet hemocyanin (DNP-KLH) as antigen intraperitoneally
into them in a dose of 100 .mu.g/mouse along with Freund's complete
adjuvant. On the 10th day after the day on which the mice were
immunized, blood was collected from the orbital venous plexus of
the animals under anesthesia with ether and examined for
anti-dintrophenyl (DNP) IgG2a antibody titer in serum by the ELISA
method.
The test compounds B, E, F, G and H were suspended in 0.5% aqueous
methyl cellulose solution and orally administered into the animals
once every day for 10 days from the day when the animals were
immunized with DNP-KLH. The medium was administered into the
control group.
The results are shown in FIG. 2.
In a dose of 0.1 mg/kg, compounds B, E, F and G significantly
inhibited anti-DNP IgG2a. In a dose of 0.1 mg/kg, compound H showed
a tendency to inhibit anti-DNP IgG2a.
The RAR.alpha.-selective agonists used here exhibited a potent
inhibitory action on production of the antibody, as demonstrated
above. Further, the action of etretinate (Tigason, Japan Roche),
that is, an agonist unselective for RAR subtype, was examined by
administration thereof in the same manner as for the
above-described test compounds. 50 mg/kg etretinate also showed a
tendency to inhibit production of the antibody in mice, but this
effect was considerably lower than that of the RAR.alpha.-selective
agonists described above (FIG. 3). Accordingly, it was suggested
that the inhibitory action of the retinoids on production of the
antibody is a unique action which is significantly augmented by
raising their selectivity for RAR.alpha..
Example 4
A Mouse Model with Spontaneous Onset of SLE
In this experiment, female (NZB.times.NZW) F1 mice were used.
Administration of each test compound was initiated at the age of 16
weeks, and blood was collected at predetermined intervals from the
orbital venous plexus of the animals under anesthesia with ether
and examined for anti-DNA (single-stranded chain: ss, double
stranded chain: ds) antibody titer in serum. Further, urine was
collected and measured for urine protein.
The test compounds A, B and D were suspended in 0.5% aqueous methyl
cellulose solution and orally administered daily once into the
animals for 6 days/week for 18 weeks. The medium was administered
into the control group.
The effect of each compound on production of anti-DNA antibody
after 16 weeks of administration (in 32-week-old animals) is shown
in FIG. 4.
Production of anti-ds DNA antibody was inhibited by 80% or more by
compounds A, B, and D, among which compound A showed significant
inhibition in a dose of 0.03 mg/kg. Production of anti-ss DNA
antibody was inhibited by 70% or more by compounds A, B, and D,
among which compounds A and B showed significant inhibition in a
dose of 0.03 mg/kg.
On the other hand, cyclosporin A which was examined in the same
manner showed, in a dose of 50 mg/kg, about 85% significant
inhibition on production of anti-ss DNA antibody, but did not
inhibit production of anti-ds DNA antibody.
The effect of each compound on the onset of albuminuria after 18
weeks of administration (in 34-week-old animals) is shown in Table
2.
TABLE 2 Effects of Compounds A, B and D on Urine Protein in
(NZB.sup.x NZW)F1 Mice Concentration Test Dose Number of of Urine
Protein (mg/ml) Level of Compound (mg/kg) Animals >10 >3
>1 >0.3 <0.3 Significance (p <0.05) Control group 8 1 3
0 1 3 Compound A 0.03 8 0 1 1 0 6 Compound B 0.03 8 0 0 0 0 8 *
Compound D 0.03 B 0 0 0 0 8 * Cyclosporin A 50 8 0 0 2 1 5
Kruskal-Wallis H Test (Dunnett type multiple comparison)
The onset of albuminuria was inhibited by compounds A, B and D in a
dose of 0.03 mg/kg, among which compounds B and D showed complete
inhibition in a dose of 0.03 mg/kg. On the other hand, cyclosporin
A showed inhibition in a dose of 50 mg/kg, though it was not
statistically significant.
From the results described above, it was revealed that the RAR
agonists, particularly RAR.alpha. agonists strongly inhibit the
production of antibody in normal rats and mice and the production
of autoantibody in autoimmune mice. It was further revealed that
glomerulonephritis and lupus nephritis in rats and mice were
significantly inhibited via this potent inhibitory action on
production of antibody.
The action of major compounds represented by the formulae (I) and
(II) and compound I regarded as RAR.alpha. agonist on each RAR
subtype receptor was examined in the following manner.
Reference Example 1
RAR Binding Assay
Cells constantly expressing RAR.alpha., .beta. and .gamma. proteins
were prepared by introducing human RAR.alpha., .beta. and .gamma.
genes into BHK (baby hamster kidney) cells. A nuclear fraction of
these cells was used to construct an experimental system for
measuring the specific binding of all-trans-retinoic acid to RAR,
and in this experimental system, the ability of each test compound
to bind to PAR was examined by measuring the degree of inhibition
of binding. Further, the ability of each test compound to bind to
each receptor subtype was compared to determine the selectivity of
the compound for RAR subtype.
(1) Experimental Method
a) Preparation of a Nuclear Extract Fraction
5.times.10.sup.8 BHK cells having the RAR gene introduced into them
were suspended in 15 ml solution A (5 mM sodium phosphate (pH 7.4),
10 mM monothioglycerol, 10% (v/v) glycerol, 1 mM phenyl methyl
sulfonyl fluoride (PMSF), 10 .mu.g/ml aprotinin, 25 .mu.g/ml
leupeptin), then homogenized therein and centrifuged, and the
supernatant was removed. The resulting pellet was suspended in 15
ml buffer B (10 mM Tris-HCl (pH 8.5), 10 mM monothioglycerol, 10%
(v/v) glycerol, 1 mM PMSF, 10 .mu.g/ml aprotinin, 25 .mu.g/ml
leupeptin, 0.4 M potassium chloride), then left at 4.degree. C. for
1 hour and ultracentrifuged at 100,000.times.g, 4.degree. C. for 1
hour. The resulting supernatant was frozen and stored as a nuclear
extract fraction at -80.degree. C. until use (Methods in
Enzymology, 189, 248).
b) Receptor Binding Assay
180 .mu.l of the extract fraction and 10 .mu.l diluted solution of
all-trans-retinoic acid or a test compound were added to each well
on a 96-well plate made of polypropylene, and further 10 .mu.l of
10 nM .sup.3 H-all-trans-retinoic acid was added thereto and left
at 4.degree. C. for 16 hours. 3% charcoal-0.3% dextran solution was
added to the reaction solution and centrifuged whereby free .sup.3
H-all-trans-retinoic acid was separated, and the count in the
supernatant was determined by a scintillation counter. The count
when a 500-fold excess of non-labeled all-trans-retinoic acid was
added was subtracted as unspecific binding from the value obtained,
to determine the amount of each compound binding specifically to
RAR.
(2) Experiment Results
The concentration (IC.sub.50) of each compound at which the binding
of .sup.3 H-all-trans-retinoic acid was inhibited by 50% was
determined and the results are shown in Tables 3-1 and 3-2.
TABLE 3-1 Receptor binding assay IC.sub.50 (nM) Compound
RAR-.alpha. RAR-.beta. RAR-.gamma. ##STR8## 1.4 340 >>500
##STR9## 1.0 500 >>500 ##STR10## 3.8 >500 >>500
##STR11## 0.6 107 195 ##STR12## <0.5 49 225 ##STR13## <0.5
160 270
TABLE 3-2 Receptor binding Assay IC.sub.50 (nM) Compound
RAR-.alpha. RAR-.beta. RAR-.gamma. ##STR14## 0.6 56 140 ##STR15##
not tested not tested not tested ##STR16## 1.0 58 130 ##STR17## not
tested not tested not tested ##STR18## 10 230 83 ##STR19## 6.4
>>500 >>500
Referential Example 2
Transcription-Promoting Activity Via RAR
A human RAR expression vector and a secretory alkali phosphatase
(PLAP) gene vector (PLAP vector) having a response sequence
integrated upstream for allowing RAR-bound PLAP to be expressed
depending on ligand, were tentatively introduced into COS-1 (renal
cell line derived from African green monkey). The PLAP, which was
produced depending on ligand and secreted into a culture liquid,
was measured by chemiluminescence techniques to examine the
transcription-promoting activity of each test compound. Further,
the ability of the test compound to promote the transcription of
each receptor subtype was compared to determine the selectivity of
the compound for RAR subtype.
(1) Experimental Method
2.5.times.10.sup.4 COS-1 cells were plated onto a 60-mm Petri dish,
and after 4 days, the cells were transformed by lipofection with 4
.mu.g expression vector for human RAR.alpha., RAR.beta. or
RAR.gamma. and 4 .mu.g PLAP vector. After 1 day, the cells were
recovered and plated at a density of 2.times.10.sup.4 cells/well on
a 96-well culture plate. After 4 hours, the medium was exchanged
with a charcoal treated FBS-containing medium, then a diluted
solution of all-trans-retinoic acid or a test compound was added
thereto, and after 36 hours, the supernatant was recovered from the
cell culture. The recovered sample was treated for 10 minutes at
65.degree. C. to eliminate unspecific activity. 15 .mu.l of the
sample was mixed with 60 .mu.l of 28 mM sodium carbonate buffer (pH
10) and reacted with 75 .mu.l of a chemifluorescent substrate
Smilight.TM. (Sumitomo Metal Industries, Ltd.) at 37.degree. C. for
30 minutes to determine the fluorescence.
(2) Experimental Results
The concentration (ED.sub.30) of each test compound showing 30%
activity, where it was assumed that the average transcriptional
activity induced by and 3 .mu.M all-trans-retinoic acid was 100%,
was determined. Then, the relative ED.sub.30 of each compound,
where it was assumed that the ED.sub.30 of all-trans-retinoic acid
for each receptor was 1, is shown as Relative ED.sub.30 * in Tables
4-1 and 4-2.
TABLE 4-1 Receptor binding assay IC.sub.50 (nM) Compound
RAR-.alpha. RAR-.beta. RAR-.gamma. ##STR20## 0.4 13 191 ##STR21##
1.0 160 1400 ##STR22## 0.33 91 790 ##STR23## 0.33 8.1 95 ##STR24##
0.39 2.8 31 ##STR25## 0.26 24 120
TABLE 4-2 Transcription promoting activity ED.sub.30 * Compound
RAR-.alpha. RAR-.beta. RAR-.gamma. ##STR26## 0.21 1.4 1.9 ##STR27##
0.2 11 170 ##STR28## 1.4 7.4 20 ##STR29## 0.85 14 89 ##STR30## 1.9
29 62 ##STR31## 6 420 7800
From the above results, it is evident that these compounds have RAR
agonist action and are particularly highly selective for
RAR.alpha..
Some other compounds are described on pp. 85-88 in the Retinoids,
2nd ed. supra, Graupner, G., Malle, G. et al., Biochemical and
Biophysical Research Communications, 179, 1554-1561, 1991, or Bruno
A. Bernard et al., Biochemical and Biophysical Research
Communications, 186, 977-983, 1992.
Reference Example 3
Involvement of RAR.alpha. in Production of Antibody in Mouse Spleen
Cells
The action of all-trans retinoic acid on in vitro production of
antibody in BALB/c mouse spleen cells was examined, and whether
this action is via RAR.alpha. or not was examined using Ro-41-5253
that is an RAR.alpha.-selective antagonist (Apfel, C., Proc. Natl.
Acad. Sci. USA, 89, 7129-7133, 1992).
(1) Experimental Method
Spleen cells from 7-week-old female BALB/c mouse were cultured at
37.degree. C. in the presence of 5% CO.sub.2 for 5 days along with
5 .mu.g/ml lipopolysaccharide (LPS) in RPMI 1640 medium containing
10% fetal bovine serum. After culture, the total amount of IgG in
the supernatant was quantified by specific ELISA techniques. The
action of all-trans retinoic acid on this production of antibody
was examined in the presence or absence of Ro-41-5253.
(2) Experimental Results
The results are shown in Table 5.
TABLE 5 Action of All-Trans-Retinoic Acid and RAR.sup..alpha.
-Selective Antagonist on in vitro Production of Antibody in Mice
Ro-41-5253 (nM) All-trans 0 20 200 2000 retinoic acid (nM) Total
IgG (ng/ml) 0 21.6 29.2 30.2 18.0 0.1 11.3 9.8 26.4 23.4 1 7.3 6.4
7.2 21.5
0.1 and 1 nM all-trans-retinoic acid inhibited in vitro production
of antibody in mice. This inhibitory action was completely
recovered by adding 200 nM and 2000 nM Ro-41-5253 that is an
RAR.alpha.-selective antagonist, thus indicating that the
inhibition of production of antibody by the retinoide is a specific
action via RAR.alpha..
Hereinafter, synthesis examples of mainly the compounds represented
by the formula (I) are described, but as a matter of course the
compounds encompassed by the present invention are not limited
thereto.
Synthetic Example 1
4-{2-[5-(5,8-dimethylnaphthalene-2-yl)pyrroryl]}benzoic acid
(A) 2-Acryloyl-5,8-dimethylnaphthalene
25 g of 5,8-dimethyltetralon was dissolved in 200 ml methanol in a
nitrogen atmosphere, and 3.0 g of sodium borohydride was added
thereto at 0.degree. C. The mixture was stirred at 0.degree. C. for
30 minutes, followed by adding an aqueous saturated ammonium
chloride solution and then water. The resulting precipitates were
filtered, washed with water and then dried to give 23.7 g alcohol
compound. 23.7 g of the alcohol compound was dissolved in 60 ml
N,N-dimethylformamide in a nitrogen atmosphere, and 25 ml
phosphorus oxychloride was added dropwise thereto at 0.degree. C.
After the completion of the dropwise addition, the reaction mixture
was heated under stirring at 100.degree. C. for 2 hours. After the
mixture was left standing for cooling to room temperature, ice-cold
water and 9 g of sodium acetate were added thereto, and the
resulting mixture was extracted with hexane (200 ml.times.4). The
organic layers were combined, washed with brine, dried over
anhydrous magnesium sulfate and then filtered. The resulting
filtrate was concentrated to give 21.3 g aldehyde compound as a
crude product.
20.9 g of the aldehyde compound was dissolved in 300 ml dioxane in
a nitrogen atmosphere, then 50.9 g of dichlorodicyanobenzoquinone
was added thereto, and the mixture was heated under reflux for 1.5
hours. After the mixture was left standing for cooling to room
temperature, 500 ml toluene was added thereto, and the resulting
precipitates were filtered off and washed with toluene several
times. The filtrate was concentrated and the resulting crude
product was purified by silica gel column chromatography to give
10.3 g of 5,8-dimethyl-2-naphthaldehyde as colorless crystals.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 2.69(s,3H), 2.76(s,3H),
7.31(d,1H,J=7.2 Hz), 7.37(d,1H,J=7.2 Hz), 7.99(dd,1H,J=1.6,8.8 Hz),
8.11(d,1H,J=8.4 Hz), 8.51(d,1H,J=1.6 z), 10.2(s,1H).
3.7 g of 5,8-dimethyl-2-naphthaldehyde was dissolved in 80 ml
ether, and 30 ml (1.0 M) vinyl magnesium bromide solution in
tetrahydrofuran was added thereto at -78.degree. C., and the
temperature was gradually raised to -30.degree. C. The solution was
quenched with an aqueous saturated ammonium chloride solution and
then extracted with ethyl acetate (100 ml.times.2). The organic
layers were combined, washed with brine, dried over anhydrous
magnesium sulfate and then filtered. The resulting filtrate was
concentrated to give 5.0 g allyl alcohol as a crude product.
The resulting product was dissolved in 30 ml dichloromethane, then
30 g activated manganese dioxide was added thereto, and the mixture
was stirred for 40 hours at room temperature. After it was filtered
through Celite, the filtrate was concentrated. The resulting crude
product was purified by silica gel column chromatography to give
1.8 g of the title compound and simultaneously 1.2 g of the
starting material was recovered.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 2.68(s,3H), 2.74(s,3H),
6.00(dd,1H,J=1.6,10.4 Hz), 6.50(dd,1H,J=1.6,17.2 Hz),
7.27-7.39(m,3H), 8.06-8.10(m,2H), 8.64(s,1H).
(B) Methyl
4-[4-(5,8-dimethylnaphthalene-2-yl)-4-oxo-butanoyl]benzoate
(Method 1)
A mixture of 1.8 g of 2-acryloyl-5,8-dimethylnaphthalene, 1.4 g of
methyl tere-aldehyde-phthalate, 0.23 g of sodium acetate, 0.23 g of
3-benzyl-5-(2-hydroxymethyl)-4-methylthiazolium chloride and 100 ml
ethanol was heated under reflux for 10 hours. The resulting
crystals were filtered, washed with ethanol, and then dried to give
1.26 g of the title compound as colorless crystals.
(Method 2)
A mixture of 1.0 g of 5,8-dimethyl-2-naphthaldehyde, 1.2 g of
methyl 4-acryloyl-benzoate, 0.28 g of
3-benzyl-5-(2-hydroxymethyl)-4-methylthiazolium chloride, 0.88 ml
triethylamine and 20 ml N,N-dimethylformamide was heated under
stirring at 70.degree. C. for 3 hours. After the reaction solution
was left standing for cooling to room temperature, water was added
thereto, and the reaction solution was extracted with ethyl acetate
(20 ml.times.3). The organic layers were combined, washed with
brine, dried over anhydrous magnesium sulfate and filtered. Then,
the filtrate was concentrated and the resulting crude crystals were
washed with a mixed solvent of n-hexane and ethyl acetate to give
0.82 g of the title compound as colorless crystals.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 2.68(s,H), 2.75(s,3H),
3.54(t,2H,J=6.4 Hz), 3.66(t,2H,J=6.4 Hz), 3.96(s,3H),
7.28(d,1H,J=7.2 Hz), 7.33(d,1H,J=7.2 Hz), 8.06-8.18(m,6H),
8.75(d,1H,J=1.6 Hz).
(C) Methyl
4-{2-[5-(5,8-dimethylnaphthalene-2-yl)pyrrolyl]}benzoate
A mixture of 0.5 g of methyl
4-[4-(5,8-dimethylnaphthalene-2-yl)-4-oxo-butanoyl]benzoate, 2.0 g
of ammonium acetate and 20 ml methanol was heated under reflux for
5 hours. The reaction solution was left standing for cooling to
room temperature, and the resulting yellow crystals were filtered,
washed with methanol and then dried to give 0.47 g methyl ester
compound as yellow crystals.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 2.67(s,3H), 2.73(s,3H),
3.93(s,3H) 6.76(m,2H), 7.18(d,1H,J=7.1 Hz), 7.23(d,1H,J=7.1 Hz),
7.63(d,2H,J=8.6 Hz), 7.74(dd,1H,J=1.6,9.2 Hz), 8.03-8.09(m,4H)
8.84(s,1H).
(D) 4-{2-[5-(5,8-Dimethylnaphthalene-2-yl)pyrrolyl]}benzoic
acid
A mixture of 0.68 g of the methyl ester compound, 40 ml ethanol and
4 ml of 5 N aqueous solution of sodium hydroxide was refluxed for 1
hour. The resulting pale yellow suspension was dissolved by adding
water thereto, followed by adding 6 N hydrochloric acid (about 3.5
ml) and 40 ml water. The resulting crystals were filtered, washed
with water and then dried to give 0.52 g of the title compound as
yellow crystals.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.59(s,3H),
2.69(s,3H), 6.81(m,2H), 7.16(d,1H,J=7.1 Hz), 7.22(d,1H,J=7.1 Hz),
7.87-8.00(m,6H), 8.36(s,1H), 11.6(s,1H).
Synthetic Example 2
4-{2-[5-(5,7-dimethylnaphthalene-2-yl)pyrrolyl]}benzoic acid
(A) 2-Acryloyl-5,7-dimethylnaphthalene
The title compound was obtained in the same manner as in Synthetic
Example 1 (A).
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 2.50(s,3H), 2.68(s,3H),
5.97(dd,1H,J=1.6,10.8 Hz), 6.49(dd,1H,J=1.6,17.2 Hz), 7.29(s,1H),
7.32(dd,1H,J=10.8,17.2 Hz), 7.59(s,8 H), 8.00(m,2H), 8.37(s,1H)
(B) Methyl
4-[4-(5,7-dimethylnaphthalene-2-yl)-4-oxo-butanoyl]benzoate
The title compound was obtained in the same manner as in Method 1
of Synthetic Example 1 (B).
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 2.51(s,3H), 2.6(s,3H),
3.53(t,2H,J=6.1 Hz), 3.63(t,2H,J=6.1 Hz), 3.96(s,3H), 7.30(s,1H),
7.61(s,1H), 8.01(d,1H,J=8.8 Hz), 8.03(dd,1H,J=1.6,8.8 Hz),
8.12(d,2H,J=8.8 Hz), 8.15(d,2H,J=8.8 Hz), 8.48(s,1H)
(C) Methyl
4-{2-[5-(5,7-dimethylnaphthalene-2-yl)pyrrolyl]}benzoate
The title compound was obtained in the same manner as in Synthetic
Example 1 (C).
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 2.48(s,3H), 2.67(s,3H),
3.93(s,3H), 6.72-6.78(m,2H), 7.14(s,1H), 7.49(s,1H),
7.62(d,2H,J=8.4 Hz), 7.67(dd,1H,J=1.6,8.8 Hz), 7.85(d,1H,J=1.6 Hz),
7.97(d,1H,J=8.8 Hz), 8.07(d,2H,J=8.4 Hz), 8.82(s,1H).
(D) 4-{2-[5-(5,7-Dimethylnaphthalene-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1 (D).
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHZ) .delta.; 2.42(s,3H),
2.60(s,3H), 6.79(m,2H), 7.13(s,1H), 7.48(s,1H), 7.84-7.94(m,6H),
8.21(s,1H), 11.5(s,1H)
Synthetic Example 3
4-{2-[5-(5,6,7,8-Tetramethylnaphthalene-2-yl) pyrrolyl]}benzoic
acid
(A) 2-Acryloyl-5,6,7,8-tetramethylnaphthalene
The title compound was obtained in the same manner as in Synthetic
Example 1 (A).
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 2.45(s,3H), 2.46(s,3H),
2.65(s,3H) 2.70(s,3H), 5.97(dd,1H,J=2.0,10.8 Hz),
6.50(dd,1H,J=1.6,17.2 Hz), 7.36(dd,1H,J=10.8,17.2 Hz),
7.98(dd,1H,J=1.6,8.8 Hz), 8.11(d,1H,J=8.8 Hz), 8.71(d,1H,J=1.6
Hz).
(B) Methyl
4-[4-(5,6,7,8-tetramethylnaphthalene-2-yl)-4-oxo-butanoyl]benzoate
The title compound was obtained in the same manner as in Method 1
of Synthetic Example 1 (B).
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 2.45(s,6H), 2.64(s,3H),
2.71(s,3H), 3.52(t,2H,J=6.2 Hz), 3.65(t,2H,J=6.2 Hz), 3.96(s,3H),
7.92-8.20(m,6H), 8.80(s,1H).
(C) Methyl
4-{2-[5-(5,6,7,8-tetramethylnaphthalene-2-yl)pyrrolyl]}benzoate
The title compound was obtained in the same manner as in Synthetic
Example 1 (C).
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 2.44(s,3H), 2.45(s,3H),
2.64(s,3H), 2.70(s,3H), 3.93(s,3H), 6.73(dd,1H,J=2.4,3.2 Hz),
6.77(dd,1H,J=2.4,3.2 Hz), 7.61-7.67(m,3H), 8.04-8.14(m,4H),
8.82(brs,1H)
(D) 4-{2-[5-(5,6,7,8-tetramethylnaphthalene-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1 (D).
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.37(s,3H),
2.38(s,3H), 2.56(s,3H), 2.67(s,3H), 6.79(m,2H),
7.83(dd,1H,J=1.2,8.8 Hz), 7.89(d,2H,J=8.0 Hz), 7.93(d,2H,J=8.0 Hz),
8.39(d,1H,J=1.2 Hz), 11.6(s,1H).
Synthetic Example 4
4-{2-[5-(7-Methoxy-8-methylnaphthalene-2-yl)pyrrolyl]}benzoic
acid
(A) Methyl
4-[4-(7-methoxy-8-methylnaphthalene-2-yl)-4-oxo-butanoyl]benzoate
The title compound was obtained in the same manner as in Method 2
of Synthetic Example 1 (B).
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 2.64(s,3H),
3.53(t,2H,J=6.0 Hz), 3.65(t,2H,J=6.0 Hz), 3.96(s,3H), 3.98(s,3H),
7.38(d,1H,J=9.2 Hz), 7.76(d,1H,J=9.2 Hz), 7.85(d,1H,J=8.8 Hz),
7.93(dd,1H,J=1.6,8.8 Hz), 8.12(d,2H,J=8.8 Hz), 8.15(d,2H,J=8.8 Hz),
8.71(m,1H).
(B) Methyl
4-{2-[5-(7-methoxy-8-methylnaphthalene-2-yl)pyrrolyl]}benzoate
The title compound was obtained in the same manner as in Synthetic
Example 1 (C).
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 2.62(s,3H), 3.94(s,3H),
3.97(s,3H), 6.73-6.78(m,2H), 7.24(d,1H,J=8.8 Hz),
7.56(dd,1H,J=2.0,8.4 Hz), 7.63(d,2H,J=8.4 Hz), 7.70(d,1H,J=8.8 Hz),
7.81(d,1H,J=8.4 Hz), 8.02(s,1H), 8.07(d,2H,J=8.4 Hz),
8.83(brs,1H).
(C) 4-{2-[5-(7-methoxy-8-methylnaphthalene-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1 (D).
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.56(s,3H),
3.90(s,3H), 6.81(d,2H,J=2.2 Hz), 7.33(d,1H,J=8.9 Hz),
7.72-7.77(m,2H), 7.82(d,1H,J=8.4 Hz), 7.90(d,2H,J=8.8 Hz),
7.93(d,2H,J=8.8 Hz), 8.30(s,1H), 11.6(s,1H).
Synthetic Example 5
4-{2-[5-(7-Methoxy-8-ethylnaphthalene-2-yl)pyrrolyl]}benzoic
acid
(A) Methyl
4-[4-(7-methoxy-8-ethylnaphthalene-2-yl)-4-oxo-butanoyl]benzoate
The title compound was obtained in the same manner as in Method 2
of Synthetic Example 1 (B).
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 1.27(t,3H,J=7.4 Hz),
3.18(q,2H,J=7.4 Hz), 3.54(t,2H,J=6.1 Hz), 3.64(t,2H,J=6.1 Hz),
3.96(s,3H), 3.98(s,3H), 7.39(d,1H,J=9.2 Hz), 7.76(d,2H,J=9.2 Hz),
7.85(d,1H,J=8.4 Hz), 7.92(dd,1H,J=1.6,8.4 Hz), 8.13(d,2H,J=8.4 Hz),
8.16(d,2H,J=8.4 Hz), 8.72(s,1H).
(B) Methyl
4-{2-[5-(7-methoxy-8-ethylnaphthalene-2-yl)pyrrolyl]}benzoate
The title compound was obtained in the same manner as in Synthetic
Example 1 (C).
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 1.29(t,3H,J=7.5 Hz),
3.16(q,2H,J=7.5 Hz), 3.94(s,3H), 3.97(s,3H), 6.73-6.78(m,2H),
7.24(d,2H,J=8.8 Hz), 7.54(dd,2H,J=2.0,8.4 Hz), 7.63(d,2H,J=8.0 Hz),
7.70(d,1H,J=8.8 Hz), 7.82(d,1H,J=8.4 Hz), 8.04(s,1H),
8.07(d,2H,J=8.0 Hz), 8.82(brs,1H)
(C) 4-{2-[5-(7-Methoxy-8-ethylnaphthalene-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1 (D).
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.18(t,3H,J=7.6 Hz),
3.14(q,2H,J=7.6 Hz), 3.91(s,3H), 6.81(m,2H), 7.33(d,1H,J=8.8 Hz),
7.74(d,2H,J=8.8 Hz), 7.83(d,1H,J=8.8 Hz), 7.91(d,2H,J=8.4 Hz),
7.94(d,2H,J=8.4 Hz), 8.28(s,1H) 18.6(s,1H)
Synthetic Example 6
4-{2-[5-(8-Methylnaphthalene-2-yl)pyrrolyl]}benzoic acid
(A) Methyl
4-[4-(8-methylnaphthalene-2-yl)-4-oxo-butanoyl]benzoate
The title compound was obtained in the same manner as in Method 2
of Synthetic Example 1 (B).
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 2.79(s,3H),
3.54(t,2H,J=6.4 Hz), 3.66(t,2H,J=6.4 Hz), 3.96(s,3H),
7.40(d,1H,J=8.0 Hz), 7.50(t,1H,J=8.0 Hz), 7.74(d,1H,J=8.0 Hz),
7.92(d,1H,J=8.4 Hz), 8.08(dd,1H,J=2.0,8.4 Hz), 8.12(d,2H,J=8.8 Hz),
8.16(d,2H,J=8.8 Hz), 8.75(s,1H).
(B) Methyl 4-{2-[5-(8-methylnaphthalene-2-yl)pyrrolyl]}benzoate
The title compound was obtained in the same manner as in Synthetic
Example 1 (C).
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 2.76(s,3H), 3.94(s,3H),
6.74-6.78(m,2H), 7.34-7.36(m,2H), 7.64(d,2H,J=8.4 Hz),
7.68-7.72(m,2H), 7.88(d,1H,J=8.4 Hz), 8.06-8.10(m,3H),
8.84(brs,1H).
(C) 4-{2-[5-(8-Methylnaphthalene-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1 (D).
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.73(s,3H),
6.83(d,2H,J=2.0 Hz), 7.30-7.36(m,2H), 7.70(m,1H), 7.86-7.96(m,6H),
8.37(s,1H), 11.6(s,1H).
Synthetic Example 7
4-{2-[5-(8-Ethylnaphthalene-2-yl)pyrrolyl]}benzoic acid
(A) Methyl
4-[4-(8-Ethylnaphthalene-2-yl)-4-oxo-butanoyl]benzoate
The title compound was obtained in the same manner as in Method 2
of Synthetic Example 1 (B).
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 1.42(t,3H,J=7.5 Hz),
3.20(q,2H,J=7.5 Hz), 3.55(t,2H,J=6.4 Hz), 3.65(t,2H,J=6.4 Hz),
3.96(s,3H), 7.42(d,1H,J=7.6 Hz), 7.53(t,1H,J=7.6 Hz),
7.74(d,1H,J=8.0 Hz), 7.92(d,1H,J=8.8 Hz), 8.07(dd,1H,J=2.0,8.8 Hz),
8.13(d,2H,J=8.4 Hz), 8.16(d,2H,J=8.4 Hz), 8.81(s,1H).
(B) Methyl 4-{2-[5-(8-ethylnaphthalene-2-yl)pyrrolyl]}benzoate
The title compound was obtained in the same manner as in Synthetic
Example 1 (C)
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 1.44(t,3H,J=7.5 Hz),
3.18(q,2H,J=7.5 Hz), 3.94(s,3H), 6.74(dd,1H,J=2.8,3.6 Hz),
6.78(dd,1H,J=2.8,3.6 Hz), 7.36-7.42(m,2H), 7.63(d,2H,J=8.4 Hz),
7.67-7.70(m,2H), 7.89(d,1H,J=8.8 Hz), 8.08(d,2H,J=8.4 Hz),
8.13(s,1H), 8.82(brs,1H).
(C) 4-{2-[5-(8-Ethylnaphthalene-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1 (D).
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.35(t,3H,J=7.5 Hz),
3.18(q,2H,J=7.5 Hz), 6.82(s,2H), 7.34-7.37(m,2H), 7.70(m,1H),
7.88-7.96(m,6H), 8.41(s,1H), 11.6(s,1H).
Synthetic Example 8
4-{2-[5-(8-isopropylnaphthalene-2-yl)pyrrolyl]}benzoic acid
(A) Methyl
4-[4-(8-isopropylnaphthalene-2-yl)-4-oxo-butanoyl]benzoate
The title compound was obtained in the same manner as in Method 2
of Synthetic Example 1 (B).
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 1.44(d,6H,J=7.0 Hz),
3.54(t,2H,J=6.4 Hz), 3.66(t,2H,J=6.4 Hz), 3.87(q,1H,J=7.0 Hz),
3.96(s,3H), 7.50(d,1H,J=8.0 Hz), 7.58(t,1H,J=8.0 Hz),
7.73(d,1H,J=8.0 Hz), 7.92(d,1H,J=8.4 Hz), 8.06(dd,1H,J=1.6,8.8 Hz),
8.12(d,2H,J=8.0 Hz), 8.16(d,2H,J=8.0 Hz), 8.90(s,1H).
(B) Methyl
4-{2-[5-(8-isopropylnaphthalene-2-yl)pyrrolyl]}benzoate
The title compound was obtained in the same manner as in Synthetic
Example 1 (C).
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 1.45(d,6H,J=7.2 Hz),
3.83(quint.,1H,J=7.2 Hz), 3.94(s,3H), 6.74(dd,1H,J=2.4,4.0 Hz),
6.78(dd,1H,J=2.4,4.0 Hz), 7.41-7.46(m,2H), 7.63(d,2H,J=8.8 Hz),
7.67-7.70(m,2H), 7.89(d,1H,J=8.4 Hz), 8.07(d,2H,J=8.8 Hz),
8.21(s,1H), 8.82(brs,1H)
(C) 4-{2-[5-(8-Isopropylnaphthalene-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1 (D).
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.37(d,6H,J=6.8 Hz),
3.96(quint.,1H,J=6.8 Hz), 6.81(m,2H), 7.37-7.44(m,2H),
7.69(d,1H,J=8.0 Hz), 7.88-7.96(m,6H), 8.48(s,1H), 11.6(s,1H).
Synthetic Example 9
4-{2-[5-(8-Isopropenylnaphthalene-2-yl)pyrrolyl]}benzoic acid
(A) Methyl
4-[4-(8-isopropenylnaphthalene-2-yl)-4-oxo-butanoyl]benzoate
The title compound was obtained in the same manner as in Method 2
of Synthetic Example 1 (B).
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 2.25(s,3H),
3.52(t,2H,J=6.4 Hz), 3.63(t,2H,J=6.4 Hz), 3.96(s,3H), 5.10(m,1H),
5.51(m,1H), 7.40(dd,1H,J=1.2,6.8 Hz), 7.56(t,1H,J=8.0 Hz),
7.79(d,1H,J=8.4 Hz), 7.91(d,1H,J=8.4 Hz), 8.06(dd,1H,J=2.0,8.8 Hz),
8.11(d,2H,J=8.4 Hz), 8.16(d,2H,J=8.4 Hz), 8.82(s,1H).
(B) Methyl
4-{2-[5-(8-isopropenylnaphthalene-2-yl)pyrrolyl]}benzoate
The title compound was obtained in the same manner as in Synthetic
Example 1 (C).
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 2.28(s,3H), 3.94(s,3H),
5.13(m,1H), 5.49(m,1H), 6.72(dd,1H,J=2.8,3.6 Hz),
6.76(dd,1H,J=2.4,3.6 Hz), 7.34(dd,1H,J=1.6,7.2 Hz),
7.41(dd,1H,J=7.2,8.0 Hz), 7.62(d,2H,J=8.8 Hz), 7.70(dd,1H,J=2.0,8.8
Hz), 7.74(d,1H,J=8.0 Hz), 7.88(d,1H,J=8.4 Hz), 8.07(d,2H,J=8.8 Hz),
8.14(s,1H), 8.79(brs,1H).
(C) 4-{2-[5-(8-Isopropenylnaphthalene-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1 (D).
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.23(s,3H),
5.07(m,1H), 5.46(m,1H), 6.70(m,1H), 6.81(m,1H), 7.31(d,1H,J=7.2
Hz), 7.40(t,1H,J=8.0 Hz), 7.88-7.95(m,6H), 8.23(s,1H),
11.6(s,1H).
Synthetic Example 10
4-{2-[5-(8-Phenylnaphthalene-2-yl)pyrrolyl]}benzoic acid
(A) Methyl
4-[4-(8-phenylnaphthalene-2-yl)-4-oxo-butanoyl]benzoate
The title compound was obtained in the same manner as in Method 2
of Synthetic Example 1 (B).
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 3.45(m,4H), 3.95(s,3H),
7.46-7.54(m,6H), 7.66(t,1H,J=8.0 Hz), 7.90(d,1H,J=8.4 Hz),
7.98(d,1H,J=8.8 Hz), 8.06-8.10(m,3H), 8.13(d,2H,J=8.4 Hz),
8.66(s,1H).
(B) Methyl 4-{2-[5-(8-phenylnaphthalene-2-yl)pyrrolyl]}benzoate
The title compound was obtained in the same manner as in Synthetic
Example 1 (C).
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 3.92(s,3H),
6.64(dd,1H,J=2.4,3.6 Hz), 6.71(dd,1H,J=2.4,3.6 Hz),
7.44(dd,1H,J=1.6,7.2 Hz), 7.48-7.56(m,8H), 7.72(dd,1H,J=1.6,8.4
Hz), 7.84(d,1H,J=8.4 Hz), 7.94(d,1H,J=8.4 Hz), 8.00(s,1H),
8.03(d,2H,J=8.4 Hz), 8.71(brs,1H).
(C) 4-{2-[5-(8-Phenylnaphthalene-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in
Synthetic Example 1 (D).
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 6.48(m,1H),
6.72(m,1H), 7.41(dd,1H,J=1.2,6.8 Hz), 7.46-7.58(m,6H)
7.78(d,2H,J=8.4 Hz), 7.88(d,2H,J=8.4 Hz), 7.91(d,1H,J=8.4 Hz),
8.00(dd,1H,J=1.2,7.8 Hz), 8.02(d,1H,J=7.8 Hz), 8.09(s,1H),
11.6(s,1H).
Synthetic Example 11
4-{2-[5-(5,8-Dimethylnaphthalene-2-yl)-1-methylpyrrolyl]}benzoic
acid
(A) Methyl
4-{2-[5-(5,8-dimethylnaphthalene-2-yl)-1-methylpyrrolyl]}benzoate
240 mg of methyl
4-{2-[5-(5,8-dimethylnaphthalene-2-yl)pyrrolyl]}benzoate was
dissolved in 5 ml N,N-dimethylformamide in a nitrogen atmosphere,
and 33 mg of (60%) sodium hydride was added thereto and stirred for
1 hour. Subsequently, 0.06 ml methyl iodide was added dropwise
thereto at 0.degree. C. and stirred at room temperature for 1 hour.
An aqueous saturated ammonium chloride solution was added thereto,
then the mixture was extracted with ethyl acetate (30 ml.times.2).
The organic layers were combined and washed with brine. It was
dried over anhydrous magnesium sulfate and then filtered, and the
filtrate was concentrated to give 300 mg of the title compound as a
crude product.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 2.70(s,6H), 3.72(s,3H),
3.94(s,3H), 6.47(d,1H,J=3.6 Hz), 6.49(d,1H,J=3.6 Hz),
7.21-7.26(m,2H), 7.59(d,2H,J=8.0 Hz), 7.66(dd,1H,J=1.6, 8.4 Hz),
8.06-8.12(m,4H).
(B)
4-{2-[5-(5,8-Dimethylnaphthalene-2-yl)-1-methylpyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1 (D).
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.62(s,3H),
2.66(s,3H), 3.71(s,3H), 6.48(m,2H), 7.24(d,1H,J=6.8 Hz),
7.26(d,1H,J=6.8 Hz), 7.68(d,2H,J=8.0 Hz), 7.73(d,1H,J=7.6 Hz),
7.99(d,2H,J=8.0 Hz), 8.07(m,2H).
Synthetic Example 12
4-{2-[5-(5,8-Dimethpylnaphthalene-2-yl)-1-isoproplpyrrolyl]}benzoic
acid
(A) Methyl
4-{2-[5-(5,8-dimethylnaphthalene-2-yl)-1-isopropylpyrrolyl]}benzoate
0.23 g of methyl
4-[4-(5,8-dimethylnaphthalene-2-yl)-4-oxo-butanoyl]benzoate was
dissolved in 4 ml acetic acid, and 4 ml isopropylamine was added
thereto at room temperature and heated under reflux for 2 hours.
After the reaction solution was left standing for cooling to room
temperature, water was added thereto, then the mixture was
extracted with ethyl acetate (30 ml.times.2). The organic layers
were combined and washed with an aqueous saturated sodium
bicarbonate solution and then with brine. It was dried over
anhydrous magnesium sulfate and filtered. The filtrate was
concentrated, and then the resulting crude product which was
purified by silica gel column chromatography to give 95 mg of the
title compound.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 1.30(d,6H,J=7.0 Hz),
2.69(s,3H), 2.71(s,3H), 3.96(s,3H), 4.58(quint.,1H,J=7.0 Hz),
6.29(s,2H), 7.23-7.28(m,2H), 7.58(d,2H,J=8.2 Hz),
7.65(dd,1H,J=1.6,8.4 Hz), 8.05(d,1H,J=8.4 Hz), 8.08-8.11(m,3H).
(B)
4-{2-[5-(5,8-Dimethylnaphthalene-2-yl)-1-isopropylpyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1 (D).
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.22(d,6H,J=7.0 Hz),
2.63(s,6H), 4.50(quint.,1H,J=7.0 Hz), 6.23(s,2H), 7.27(q,AB type,
2H,J=6.8 Hz), 7.58(d,2H,J=8.0 Hz), 7.64(dd,1H,J=1.6,8.8 Hz),
7.99(m,3H), 8.06(d,1H,J=8.8 Hz), 12.9(brs.1H).
Synthetic Example 13
4-{2-[5-(4,7-Dimethylbenzofuran-2-yl)pyrrolyl]}benzoic acid
(A) methyl
4-[4-(4,7-dimethylbenzofuran-2-yl)-4-oxo-butanoyl]benzoate
22.6 g of anhydrous potassium carbonate and 14.8 ml
bromoacetaldehyde diethyl acetal were added to 100 ml solution of
10 g 2,5-dimethylphenol in N,N-dimethylformamide and heated under
stirring at 150.degree. C. for 2.5 hours. After the mixture was
left standing for cooling to room temperature, it was extracted
with ethyl acetate. The organic layer was washed with brine and
then dried over anhydrous magnesium sulfate. The solvent was
evaporated, and the resulting residue was purified by silica gel
column chromatography to give 18 g ether compound as a colorless
oil.
The resulting oil was dissolved in 100 ml toluene, and 50 g of
polyphosphoric acid was added thereto and heated under stirring at
90.degree. C. for 1 hour in a nitrogen atmosphere. After the
mixture was left standing for cooling to room temperature, it was
poured into ice-cold water and extracted with ethyl acetate. The
organic layer was washed with brine and then dried over anhydrous
magnesium sulfate. The solvent was evaporated, and the resulting
residue was purified by silica gel column chromatography to give
3.5 g of 4,7-dimethylbenzofuran as a yellow oil.
18.4 ml n-butyl lithium (1.56 M solution in hexane) was added to 50
ml solution of 3.5 g 4,7-dimethylbenzofuran in anhydrous
tetrahydrofuran at -35.degree. C. in a nitrogen atmosphere. After
stirring for 15 minutes,5.6 ml N,N-dimethylformamide was added
dropwise thereto, and the temperature was raised to room
temperature. Ethyl acetate was added to the reaction mixture, and
the organic layer was washed with brine and then dried over
anhydrous magnesium sulfate. The solvent was evaporated, and the
resulting crude crystals were washed with n-hexane to give 2.3 g of
4,7-dimethylbenzofuran-2-carbaldehyde as apale yellow solid.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 2.53(s,6H),
7.02(d,1H,J=6.8 Hz), 7.20(d,1H,J-6.8 Hz), 7.59(s,1H),
9.85(s,1H).
Using the resulting 4,7-dimethylbenzofuran-2-carbaldehyde, the
title compound was obtained in the same manner as in Method 2 of
Synthetic Example 1 (B).
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 2.50(s,3H), 2.51(s,3H),
3.45-3.55(m,4H), 3.94(s,3H), 7.00(d,1H,J=6.8 Hz), 7.16(d,1H,J=6.8
Hz), 7.62(s,1H), 8.09(d,2H,J=8.4 Hz), 8.14(d,2H,J=8.4 Hz).
(B) Methyl 4-{2-[5-(4,7-dimethylbenzofuran-2-yl)
pyrrolyl]}benzoate
The title compound was obtained in the same manner as in Synthetic
Example 1 (C).
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 2.48(s,3H), 2.55(s,3H),
3.93(s,3H), 6.72-6.77(m,2H), 6.83(s,1H), 6,93(d,1H,J=6.8 Hz),
6.97(d,1H,J=6.8 Hz), 7.63(d,2H,J=8.4 Hz), 8.07(d,2H,J=8.4 Hz),
9.00(brs,1H).
(C) 4-{2-[5-(4,7-Dimethylbenzofuran-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1 (D).
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.43(s,3H),
2.46(s,3H), 6.71(t,1H,J=2.4 Hz), 6.84(t,1H,J=2.4 Hz),
6.92(d,1H,J=7.2 Hz), 6.96(d,1H,J=7.2 Hz), 7.23(s,1H),
7.89(d,2H,J=8.4 Hz), 7.95(d,2H,J=8.4 Hz), 11.81(brs.1H),
12.85(brs,1H).
Synthetic Example 14
4-{2-[5-(4,7-Dichlorobenzofuran-2-yl) pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 6.83(t,1H,J=2.4 Hz),
6.89(t,1H,J=2.4 Hz), 7.35(d,1H,J=7.2 Hz), 7.38(d,1H,J=7.2 Hz),
7.39(s,1H), 7.91(d,2H,J=8.4 Hz), 7.97(d,2H,J=8.4 Hz),
12.02(brs,1H), 12.86(brs,1H).
Synthetic Example 15
4-{2-[5-(7-Chlorobenzofuran-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 6.76(t,1H,J=3.2 Hz),
6.86(t,1H,J=3.2 Hz), 7.23(t,1H,J=7.6 Hz), 7.29(s,1H),
7.33(dd,1H,J=0.8, 7.6 Hz), 7.61(dd,1H,J=0.8, 7.6 Hz),
7.90(d,2H,J=8.4 Hz), 7.95(d,2H,J=8.4 Hz), 11.96(s,1H),
12.83(brs,1H).
Synthetic Example 16
4-{2-[5-(7-n-Propylbenzofuran-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 0.95(t,3H,J=7.2 Hz),
1.75(sect,2H,J=7.2 Hz), 2.87(t,2H,J=7.2 Hz), 6.71(t,1H,J=3.2 Hz),
6.84(t,1H,J=3.2 Hz), 7.06(dd,1H,J=1.2,7.6 Hz), 7.13(t,1H,J=7.6 Hz),
7.17(s,1H), 7.44(dd,1H,J=1.2,7.6 Hz), 7.88(d,2H,J=8.4 Hz),
7.95(d,2H,J=8.4 Hz), 11.82(s,1H), 12.80(brs,1H).
Synthetic Example 17
4-{2-[5-(4-Methyl-7-ethylbenzofuran-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.29(t,3H,J=7.6 Hz),
2.45(s,3H), 2.88(q,2H,J=7.6 Hz), 6.70(m,1H), 6.83(m,1H),
6.95(d,1H,J=7.2 Hz), 6.98(d,1H,J=7.2 Hz), 7.23(s,1H),
7.89(d,2H,J=8.8 Hz), 7.94(d,2H,J=8.8 Hz), 11.80(s,1H),
12.82(brs,1H).
Snythetic Example 18
4-{2-[5-(4-Methyl-7-7-n-propylbenzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 0.93(t,3H), J=7.6
Hz), 1.73(sect,2H,J=7.6 Hz), 2.45(s,3H), 2.83(t,2H,J=7.6 Hz),
6.70(m,1H), 6.83(m,1H), 6.94(d,1H,J=7.2 Hz), 6.95(d,1H,J=7.2 Hz),
7.22(s,1H), 7.89(d,2H,J=8.4 Hz), 7.94(d,2H,J=8.4 Hz), 11.81(s,1H),
12.83(brs,1H).
Synthetic Example 19
4-{2-[5-(4-Chloro-7-methylbenzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.48(s,3H),
6.78-6.82(m,1H) 6.85-6.88(m,1H), 7.09(d,1H,J=7.6 Hz),
7.21(d,1H,J=7.6 Hz), 7.29(s,1H), 7.90(d,2H,J=8.4 Hz),
7.96(d,2H,J=8.4 Hz), 11.91(brs,1H).
Synthetic Example 20
4-{2-[5-(4-Chloro-7-ethylbenzofuran-2-yl)pyrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.30(t,3H,J=7.5 Hz),
2.90(q,2H,J=7.5 Hz), 6.79(dd,1H,J=2.4, 3.6 Hz), 6.86(dd,1H,J=2.4,
3.6 Hz), 7.11(d,1H,J=8.0 Hz), 7.23(d,1H,J=8.0 Hz), 7.29(s,1H),
7.89(d,2H,J=8.8 Hz), 7.95(d,2H,J=8.4 Hz), 11.90(brs,1H).
Synthetic Example 21
4-{2-[5-(4-Chloro-7-n-porpylbenzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 0.94(t,3H,J=7.2 Hz),
1.68-1.77(m,2H), 2.86(t,2H,J=7.2 Hz), 6.77-6.80(m,1H),
6.84-6.88(m,1H), 7.09(d,1H,J=8.4 Hz), 7.22(d,1H,J=8.4 Hz),
7.28(s,1H), 7.89(d,2H,J=8.8 Hz), 7.95(d,2H,J=8.8 Hz),
11.90(brs,1H).
Synthetic Example 22
4-{2-[5-(5-Chloro-7-methylbenzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.48(s,3H),
6.74-6.77(m,1H), 6.83-6.86(m,1H), 7.10-7.13(m,1H), 7.17(s,1H),
7.52-7.54(m,1H), 7.88(d,2H,J=8.4 Hz), 7.95(d,2H,J=8.8 Hz),
11.89(brs,1H).
Synthetic Example 23
4-{2-[5-(5-Chloro-7-ethylbenzofuran-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.30(t,3H,J=7.6 Hz),
2.90(q,2H,J=7.6 Hz), 6.74(dd,1H,J=1.6, 3.6 Hz),
6.84(dd,1H,J=1.2,3.6 Hz), 7.12(s,1H), 7.17(s,1H), 7.54(s,1H),
7.89(d,2H,J=8.4 Hz), 7.94(d,2H,J=8.4 Hz), 11.89(s,1H).
Synthetic Example 24
4-{2-[5-(5-Chloro-7-n-propylbenzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.94(t,3H,J=7.6 Hz),
1.74(sect,2H,J=7.6 Hz), 2.86(t,2H,J=7.6 Hz), 6.74(m,1H),
6.84(m,1H), 7.10(d,1H,J=2.4 Hz), 7.18(s,1H), 7.54(d,1H,J=2.4 Hz),
7.89(d,2H,J=8.4 Hz), 7.94(d,2H,J=8.4 Hz), 11.91(s,1H).
Synthetic Example 25
4-{2-[5-(5-Fluoro-7-ethylbenzofuran-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.31(t,3H,J=7.6 Hz),
2.91(q,2H,J=7.6 Hz), 6.74(t,1H,J=3.6 Hz), 6.84(t,1H,J=3.2 Hz),
6.94(dd,1H,J=2.0,10.0 Hz), 7.25(dd,1H,J=2.4, 8.8 Hz), 7.29(s,1H),
7.94(brs,4H), 12.04(brs,1H).
Synthetic Example 26
4-{2-[5-(5-Fluoro-7-n-propylbenzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 0.95(t,3H,J=7.2 Hz),
1.74(q,2H,J=7.2 Hz), 2.86(t,2H,J=7.2 Hz), 6.73(dd,1H,J=2.0,3.6 Hz),
6.84(dd,1H,J=2.4,3.6 Hz), 6.93(dd,1H,J=2.0,10.4 Hz),
7.22-7.28(m,2H), 7.90-7.96(brs,4H), 12.00(s,1H).
Synthetic Example 27
4-{2-[5-(4,7-Difluorobenzofuran-2-yl)pyrrolyl]}benzoic acid
10 g of 2,5-difluorophenol was dissolved in 120 ml
dimethylformaldehyde, 21 g of potassium carbonate and 8.57 ml allyl
bromide were added in this order thereto at room temperature and
then the resulting mixture was stirred at 80.degree. C. for 1 hour.
After water was added to the reaction mixture, it was extracted
with ethyl acetate. The organic layer was washed with brine, dried
over anhydrous magnesium sulfate and then evaporated. The resulting
residue was subjected to silica gel chromatography (developing
solvent: 5% ethyl acetate/n-hexane) to give 13 g of
2,5-difluorophenol allyl ether as a colorless oil.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 4.58(d,2H,J=5.2 Hz),
5.33(dd,1H,J=2.4,8.4 Hz), 5.44(dd,1H, d, J=2.4,17.2 Hz),
5.98-6.10(m,1H), 6.55-6.60(m,1H), 6.70(ddd,1H,J=3.2,6.8,10.0 Hz),
7.01(ddd,1H,J=5.2,8.8,10.0 Hz).
13 g 2,5-difluorophenol allyl ether was dissolved in 90 ml
N,N-dimethylaniline and stirred at 170.degree. C. for 5 hours in a
nitrogen stream. The reaction solution was poured into 10% aqueous
hydrogen chloride solution and then extracted with ethyl acetate.
The organic layer was washed with brine, dried over anhydrous
magnesium sulfate and then evaporated The resulting residue was
subjected to silica gel chromatography (developing solvent: 7%
ethyl acetate/n-hexane) to give 7.8 g of 2-allyl-3,6-difluorophenol
as a colorless oil.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 3.44(dd,2H,J=1.2,6.0
Hz), 5.05-5.09(m,1H), 5.26-5.28(m,1H), 5.90-5.99(m,1H),
6.56(dt,1H,J=4.4,9.2 Hz), 6.91(dt,1H,J=5.2,9.2 Hz).
7.0 g 2-allyl-3,6-difluorophenol was dissolved in 100 ml
dichloromethane, and after 3-chloroperbenzoic acid was added
thereto at 0.degree. C. in a nitrogen stream, the mixture was
stirred at room temperature for 2 hours. After water was added to
the reaction mixture, it was extracted with dichloromethane. The
organic layer was washed with a saturated aqueous sodium
bicarbonate and brine, dried over anhydrous magnesium sulfate and
then evaporated to give 7.2 g epoxide as a crude product. The
resulting 7.2 g of epoxide was dissolved in 30 ml dimethyl
sulfoxide and 10 ml water, potassium hydroxide was added thereto at
room temperature and then the mixture was stirred for 4 hours.
Ethyl acetate was added to the reaction mixture, and the organic
layer was washed with brine. It was dried over anhydrous magnesium
sulfate and then evaporated, and the resulting residue was
subjected to silica gel chromatography (developing solvent: 20%
ethyl acetate/n-hexane) to give 1.2 g
fluoro-2,3-dihydro-2-hydroxymethylbenzofuran as a colorless
oil.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 3.25(dd,1H,J=6.7,16
Hz), 3.33(dd,1H,J=8.0,16.0 Hz), 3.75-3.83(m,1H), 3.90-3.97(m,1H),
5.04-5.13(m,1H), 6.49(ddd,1H,J=2.8,10.0,11.2 Hz),
6.87(dt,1H,J=4.4,10.0 Hz).
4,7-Difluoro-2,3-dihydro-2-hydroxymethylbenzofuran (1.2 g) was
dissolved in 6 ml pyridine, then 0.73 ml acetic anhydride was added
thereto at 0.degree. C. in a nitrogen stream, and the mixture was
stirred at room temperature for 17 hours. The reaction solution was
poured into 10% aqueous hydrogen chloride and extracted with ethyl
acetate. The organic layer was washed with brine, dried over
anhydrous magnesium sulfate and then evaporated. The resulting
residue was subjected to silica gel chromatography (developing
solvent: 5% ethyl acetate/n-hexane) to give 750 mg
2-acetoxymethyl-4,7-difluoro-2,3-dihydrobenzofuran as a colorless
oil.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 2.17(s,3H),
3.08(dd,1H,J=7.2,15.6 Hz), 3.39(dd,1H,J=10.0,15.6 Hz),
4.28(dd,1H,J=6.4,12 Hz), 4.36(dd,1H,J=3.6,12 Hz), 5.13-5.20(m,1H),
6.51(ddd,1H,J=2.8,10.0,10.8 Hz), 6.89(dt,1H,J=4.4,10.0 Hz).
750 mg 2-acetoxymethyl-4,7-difluoro-2,3-dihydrobenzofuran was
dissolved in 15 ml carbon tetrachloride, 582 mg of N-bromosuccinic
imide and 10 mg of azodiisopropylnitrile were added in this order
thereto, and then the mixture was heated under reflux for 1 hour.
The reaction solution was filtered through a glass filter, and then
the resulting filtrate was concentrated. To the resulting oil was
added ethyl acetate. The organic layer was washed with brine, dried
over anhydrous magnesium sulfate and then evaporated to give 800 mg
bromide as a crude product. The resulting bromide was dissolved in
6 ml tert-butyl alcohol, and 3.3 ml potassium tert-butoxide (1.0 M
solution in tert-butyl alcohol) was added thereto at room
temperature in a nitrogen stream and stirred at room temperature
for 2 hours. Ethyl acetate was added to the reaction solution, and
the organic layer was washed with brine. It was dried over
anhydrous magnesium sulfate and then evaporated, and the resulting
residue was subjected to silica gel chromatography (developing
solvent: 10% ethyl acetateln-hexane) to give 252 mg
2-acetoxymethyl-4,7-difluorobenzofuran as a colorless oil.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 2.14(s,3H), 5.20(s,2H),
6.84(dt,1H,J=3.2,8.8 Hz), 6.89(d,1H,J=2.4 Hz),
6.98(ddd,1H,J=4.0,8.8 Hz).
2-Acetoxymethyl-4,7-difluorobenzofuran (252 mg) was dissolved in 5
ml methanol, 455 mg potassium carbonate was added thereto at room
temperature, and the mixture was stirred for 2 hours at the same
temperature. Ethyl acetate was added to the reaction solution, and
the organic layer was washed with brine. It was dried over
anhydrous magnesium sulfate and then evaporated, and the resulting
residue was subjected to silica gel chromatography (developing
solvent: 5% ethyl acetate/n-hexane) to give 161 mg
4,7-difluoro-2-hydroxybenzofuran as a colorless oil.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 4.80(d,2H,J=4.0 Hz),
6.80(d,1H,J=2.8 Hz), 6.83(dt,1H,J=2.8,8.4 Hz),
6.95(ddd,1H,J=4.0,8.4,10.0 Hz).
Oxazalyl chloride (0.26 ml) was added to 0.42 ml dimethyl sulfoxide
and 7 ml dichloromethane at -78.degree. C. and stirred for 3
minutes at the same temperature. 272 mg of the
4,7-difluoro-2-hydroxybenzofuran was added thereto at the same
temperature and stirred for 40 minutes. After 1.2 ml triethylamine
was added to the reaction mixture, the temperature was raised to
room temperature, and the mixture was stirred at room temperature
for 30 minutes. After water was added to the reaction mixture, it
was extracted with ethyl acetate. The organic layer was washed with
brine, dried over anhydrous magnesium sulfate and then evaporated.
The resulting residue was subjected to silica gel chromatography
(developing solvent: 5% ethyl acetate/n-hexane) to give 169 mg of
4,7-difluorobenzofuran-2-carbaldehyde as a colorless solid.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 6.96(dt,1H,J=2.8,8.8
Hz), 7.21(ddd,1H,J=4.0,8.8,9.6 Hz), 7.66(d,1H,J=2.4 Hz),
9.92(s,1H).
The title compound was obtained by use of the aldehyde compound in
the same manner as in Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 6.82(dd,1H,J=2.4,3.6
Hz), 6.86(dd,1H,J=2.4,3.6 Hz), 7.08(dd,1H,J=3.2,8.8 Hz),
7.19(dd,1H,J=3.2,8.8 Hz), 7.42(d,1H,J=2.4 Hz), 7.92(d,2H,J=8.4 Hz),
7.96(d,2H,J=8.4 Hz), 12.08(s,1H).
Synthetic Example 28
4-{2-[5-(5-Chloro-7-isopropenylbenzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.25(s,3H),
5.48(s,1H), 5.93(s,1H), 6.74(m,1H), 6.84(m,1H), 7.23(m,2H),
7.67(m,1H), 7.88(d,2H,J=8.4 Hz), 7.94(d,2H,J=8.4 Hz), 11.96(s,1H),
12.87(brs,1H).
Synthetic Example 29
4-{2-[5-(5-Chloro-7-isopropylbenzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.34(d,6H,J=7.2 Hz),
3.44(quint,1H,J=7.2 Hz), 6.75(m,1H), 6.84(m,1H), 7.12(m,1H),
7.18(d,1H,J=0.8 Hz), 7.54(dd,1H,J=1.2,2.0 Hz), 7.89(d,2H,J=8.0 Hz),
7.94(d,2H,J=8.0 Hz), 11.91(s,1H), 12.88(brs,1H).
Synthetic Example 30
4-{2-[5-(5-Methyl-7-n-propylbenzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 0.94(t,3H,J=7.2 Hz),
1.74(sect,2H,J=7.2 Hz), 2.34(s,3H), 2.82(t,2H,J=7.2 Hz),
6.68(m,1H), 6.83(m,1H), 6.88(s,1H), 7.11(s,1H), 7.22(s,1H),
7.88(d,2H,J=8.4 Hz), 7.94(d,2H,J=8.4 Hz), 11.81(s,1H),
12.86(brs,1H).
Synthetic Example 31
4-{2-[5-(5-Methyl-7-isopropenylbenzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.26(s,3H),
2.38(s,3H), 5.40(s,1H), 5.88(s,1H), 6.68(m,1H), 6.83(m,1H),
7.08(s,1H), 7.15(s,1H), 7.36(s,1H), 7.88(d,2H,J=8.4 Hz),
7.94(d,2H,J=8.4 Hz), 11.84(s,1H), 12.83(brs,1H).
Synthetic Example 32
4-{2-[5-(5-Methyl-7-isopropylbenzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.34(d,6H,J=6.8 Hz),
2.35(s,3H), 3.40(quint,1H,J=6.8 Hz), 6.68(dd,1H,J=2.4,3.6 Hz),
6.82(dd,1H,J=2.4,3.6 Hz), 6.92(s,1H), 7.10(s,1H), 7.22(s,1H),
7.88(d,2H,J=8.8 Hz), 7.94(d,2H,J=8.8 Hz), 11.79(s,1H),
12.82(brs,1H).
Synthetic Example 33
4-{2-[5-(5-Methyl-7-ethylbenzofuran-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.30(t,3H,J=7.6 Hz),
2.35(s,3H), 2.87(q,2H,J=7.6 Hz), 6.69(m,1H), 6.83(m,1H),
6.90(s,1H), 7.11(s,1H), 7.22(s,1H), 7.88(d,2H,J=7.6 Hz),
7.94(d,2H,J=7.6 Hz), 11.81(s,1H), 12.84(brs,1H).
Synthetic Example 34
4-{2-[5-(4-Methyl-7-isopropylbenzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.33(d,6H,J=6.8 Hz),
2.44(s,3H), 3.41(quint,1H,J=6.8 Hz), 6.70(m,1H), 6.84(m,1H),
6.95(d,1H,J=7.6 Hz), 7.00(d,1H,J=7.6 Hz), 7.22(s,1H),
7.88(d,2H,J=7.6 Hz), 7.94(d,2H,J=7.6 Hz), 11.80(s,1H),
12.84(brs,1H).
Synthetic Example 35
4-{2-[5-(5-Methoxy-7-ethylbenzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.30(t,3H,J=7.6 Hz),
2.87(q,1H,J=7.6 Hz), 3.77(s,3H), 6.69(m,2H), 6.83(dd,1H,J=2.4,3.6
Hz), 6.97(d,1H,J=2.4 Hz), 7.12(s,1H), 7.88(d,2H,J=8.4 Hz),
7.94(d,2H,J=8.4 Hz), 11.80(s,1H), 12.83(brs,1H).
Synthetic Example 36
4-{2-[5-(5-Methoxy-7-n-propylbenzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 0.94(t,3H,J=7.2 Hz),
1.74(sect,2H,J=7.6 Hz), 2.82(t,2H,J=7.6 Hz), 3.76(s,3H),
6.66(s,1H), 6.68(m,1H), 6.83(m,1H), 6.98(s,1H), 7.12(d,1H,J=1.6
Hz), 7.88(d,2H,J=8.4 Hz), 7.94(d,2H,J=8.4 Hz), 11.80(s,1H),
12.83(brs,1H).
Synthetic Example 37
4-{2-[5-(4-Methoxy-7-ethylbenzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.28(t,3H,J=7.6 Hz),
2.84(q,2H,J=7.6 Hz), 3.87(s,3H), 6.68(s,1H), 6.69(d,1H,J=8.0 Hz),
6.82(s,1H), 7.01(d,1H,J=8.0 Hz), 7.23(s,1H), 7.87(d,2H,J=8.0 Hz),
7.94(d,2H,J=8.0 Hz), 11.73(s,1H) , 12.80(brs,1H).
Synthetic Example 38
4-{2-[5-(4-Methoxy-7-n-propylbenzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 0.93(t,3H,J=7.6 Hz),
1.70(m,2H), 2.79(t,2H,J=7.6 Hz), 3.88(s,3H), 6.68(m,2H),
6.82(m,1H), 6.99(d,1H,J=8.0 Hz), 7.23(s,1H), 7.87(d,2H,J=8.0 Hz),
7.93(d,2H,J=8.0 Hz), 11.73(s,1H), 12.68(brs,1H).
Synthetic Example 39
4-{2-[5-(Indano[4,5-b]furan-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.14(quint,2H,J=7.2
Hz), 2.97(t,2H,J=7.2 Hz), 3.10(t,2H,J=7.2 Hz), 6.68(m,1H),
6.82(m,1H), 7.12(d,1H,J=7.6 Hz), 7.17(s,1H), 7.39(d,1H,J=7.6 Hz),
7.88(d,2H,J=7.6 Hz), 7.94(d,2H,J=7.6 Hz), 11.81(s,1H),
12.82(brs,1H).
Synthetic Example 40
4-{2-[5-(6,7-dimethylbenzofuran-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.30(s,3H),
2.42(s,3H), 6.69-6.72(m,1H), 6.81-6.84(m,1H), 7.02(d,1H,J=8.4 Hz),
7.11(s,1H), 7.30(d,1H,J=8.4 Hz), 7.88(d,2H,J=8.4 Hz),
7.94(d,2H,J=8.4 Hz), 11.78(s,1H), 12.80(brs,1H).
Synthetic Example 41
4-{2-[5-(7-Phenoxybenzofuran-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 6.56-6.59(m,1H),
6.79-6.84(m,2H), 7.07-7.21(m,4H), 7.25(s,1H), 7.37-7.44(m,3H),
7.87(d,2H,J=8.4 Hz), 7.93(d,2H,J=8.4 Hz), 11.91(s,1H),
12.82(brs,1H).
Synthetic Example 42
4-{2-[5-(4-Fluoro-7-chlorobenzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 6.79-6.82(m,1H),
6.86-6.89(m,1H), 7.14(t,1H,J=8.8 Hz), 7.37(dd,1H,J=4.4, 8.4 HZ),
7.38(s,1H), 7.90(d,2H,J=8.4 Hz), 7.96(d,2H,J=8.4 Hz), 11.97(d,1H),
12.86(brs,1H).
Synthetic Example 43
4-{2-[5-(5-Fluoro-7-chlorobenzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 6.76-6.80(m,1H),
6.84-6.88(m,1H), 7.29(s,1H), 7.34(dd,1H,J=2.4,8.4 Hz),
7.51(dd,1H,J=2.4,8.4 Hz), 7.90(d,2H,J=8.4 Hz), 7.96(d,2H,J=8.4 Hz),
12.00(s,1H), 12.86(brs,1H).
Synthetic Example 44
4-{2-[5-(7-Trifluoromethylbenzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 6.72-6.75(m,1H),
6.85-6.88(m,1H), 7.35(s,1H), 7.40(t,1H,J=7.6 Hz), 7.56(d,1H,J=7.6
Hz), 7.89(d,2H,J=8.4 Hz), 7.96(d,2H,J=8.4 Hz), 11.98(s,1H),
12.83(brs,1H).
Synthetic Example 45
4-{2-[5-(5,7-Dichlorobenzofuran-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 6.76-6.81(m,1H),
6.84-6.89(m,1H), 7.28(s,1H), 7.46(d,1H,J=2.0 Hz), 7.76(d,1H,J=2.0
Hz), 7.89(d,2H,J=8.4 Hz), 7.95(d,2H,J=8.4 Hz), 12.00(brs,1H).
Synthetic Example 46
4-{2-[5-(4,7-Dichloro-3-methylbenzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.56(s,3H),
6.69-6.73(m,1H), 6.89-6.93(m,1H), 7.30(d,1H,J=8.8 Hz),
7.39(d,1H,J=8.8 Hz), 7.94(s,4H), 11.97(brs,1H), 12.82(brs,1H).
Synthetic Example 47
4-{2-[5-(3,4,7-Trimethylbenzofuran-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.50(s,3H),
2.53(s,3H), 2.59(s,3H), 6.57(brs,1H), 6.82-6.88(m,2H),
6.94(d,1H,J=7.2 Hz), 7.90(s,4H), 11.70(brs,1H), 12.80(brs,1H).
Synthetic Example 48
4-{2-[5-(7-Isopropylbenzofuran-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.36(d,6H,J=7.6 Hz),
3.45(quint,1H,J=7.6 Hz), 6.70-6.73(m,1H), 6.83-6.86(m,1H),
7.09-7.16(m,2H), 7.17(s,1H), 7.43(d,1H,J=7.6 Hz), 7.88(d,2H,J=8.4
Hz), 7.95(d,2H,J=8.4 Hz), 11.83(s,1H), 12.82(brs,1H).
Synthetic Example 49
4-{2-[5-(4,6-Dimethylbenzofuran-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.35(s,3H),
2.43(s,3H), 6.65-6.68(m,1H), 6.81-6.84(m,1H), 6.87(brs,1H),
7.16-7.21(m,2H), 7.88(d,2H,J=8.4 Hz), 7.93(d,2H,J=8.4 Hz),
11.82(s,1H), 12.79(brs,1H).
Synthetic Example 50
4-{2-[5-(5,7-Dimethylbenzofuran-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.32(s,3H),
2.45(s,3H), 6.68-6.71(m,1H), 6.80-6.83(m,1H), 6.88(d,1H,J=1.2 Hz),
7.10(s,1H), 7.20(d,1H,J=1.2 Hz), 7.86(d,2H,J=8.4 Hz),
7.93(d,2H,J=8.4 Hz), 11.78(s,1H), 12.80(brs,1H).
Synthetic Example 51
4-{2-[5-(4-Methoxy-7-mehtylbenzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.41(s,3H),
3.86(s,3H), 6.66-6.70(m,2H), 6.81-6.85(m,1H), 6.99(d,1H,J=7.6 Hz),
7.24(s,1H), 7.88(d,2H,J=8.4 Hz), 7.94(d,2H,J=8.4 Hz), 11.75(s,1H),
12.80(brs,1H).
Synthetic Example 52
4-{2-[5-(7-Ethoxybenzofuran-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.40(t,3H,J=7.6 Hz),
4.25(q,2H,J=7.6 Hz), 6.68-6.71(m,1H), 6.81-6.84(m,1H),
6.87(d,1H,J=7.6 Hz), 7.12(t,1H,J=7.6 Hz), 7.16-7.19(m,2H),
7.89(d,2H,J=8.4 Hz), 7.94(d,2H,J=8.4 Hz), 11.87(s,1H),
12.78(brs,1H).
Synthetic Example 53
4-{2-[5-(7-Chloro-4-methylbenzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 6.73-6.76(m,1H),
6.84-6.87(m,1H), 7.05(d,1H,J=8.0 Hz), 7.22(d,1H,J=8.0 Hz),
7.33(s,1H), 7.90(d,2H,J=8.4 Hz), 7.95(d,2H,J=8.4 Hz), 11.93(s,1H),
12.88(brs,1H).
Synthetic Example 54
4-{2-[5-(7-Methoxybenzofuran-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 3.93(s,3H),
6.68-6.71(m,1H), 6.81-6.84(m,1H), 6.88(dd,1H,J=1.2, 8.0 Hz),
7.14(t,1H,J=8.0 Hz), 7.18(s,1H), 7.19(dd,1H,J=1.2, 8.0 Hz),
7.89(d,2H,J=8.4 Hz), 7.94(d,2H,J=8.4 Hz), 11.87(s,1H),
12.84(brs,1H).
Synthetic Example 55
4-{2-[5-(7-Ethylbenzofuran-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.30(t,3H,J=7.6 Hz),
2.90(q,2H,J=7.6 Hz), 6.70-6.73(m,1H), 6.82-6.85(m,1H),
7.08(dd,1H,J=0.8,8.0 Hz), 7.14(t,1H,J=8.0 Hz), 7.44(dd,1H,J=0.8,8.0
Hz), 7.88(d,2H,J=8.4 Hz), 7.94(d,2H,J=8.4 Hz), 11.82(s,1H),
12.83(brs,1H).
Synthetic Example 56
4-{2-[5-(7-Phenylbenzofuran-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 6.68-6.71(m,1H),
6.83-6.86(m,1H), 7.28(s,1H), 7.32(t,1H,J=7.6 Hz), 7.40-7.48(m,2H),
7.56(t,2H,J=7.6 Hz), 7.63(d,1H,J=7.6 Hz), 7.88(d,2H,J=8.4 Hz),
7.92-7.98(m,4H), 11.90(s,1H), 12.84(brs,1H).
Synthetic Example 57
4-{2-[5-(7-Methylbenzofuran-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.52(s,3H),
6.71-6.74(m,1H), 6.83-6.86(m,1H), 7.06(d,1H, , J=7.2 Hz),
7.12(t,1H,J=7.2 Hz), 7.18(s,1H), 7.43(d,1H,J=7.2 Hz),
7.89(d,2H,J=8.4 Hz), 7.95(d,2H,J=8.4 Hz), 11.83(s,1H),
12.82(brs,1H).
Synthetic Example 58
4-{2-[5-(4,5-Dimethylbenzofuran-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.34(s,3H),
2.46(s,3H), 6.70(dd,1H,J=2.4,3.6 Hz), 6.83(dd,1H,J=2.4,3.6 Hz),
7.11(s,1H), 7.22(s,1H), 7.87-7.95(m,4H), 11.80(s,1H),
12.79(s,1H).
Synthetic Example 59
4-{2-[5-(4-Methylbenzofuran-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.51(s,3H),
6.72-6.73(m,1H), 6.84-6.85(m,1H), 7.06(d,1H,J=7.2 Hz),
7.12(dd,1H,J=5.2, 5.2 Hz), 7.10(s,1H), 7.44(d,1H,J=7.6 Hz),
7.89(d,2H,J=8.4 Hz), 7.95(d,2H,J=8.4 Hz).
Synthetic Example 60
4-{2-[5-(4-Chlorobenzofuran-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 6.78-6.80(m,1H),
6.86-6.87(m,1H), 7.24-7.33(m,3H), 7.57(d,1H,J=8.0 Hz),
7.92(d,2H,J=8.4 Hz), 7.95(d,2H,J=8.4 Hz), 11.97(s,1H),
12.87(brs,1H).
Synthetic Example 61
4-{2-[5-(5-Chlorobenzofuran-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 6.74-6.75(m,1H),
6.82-6.84(m,1H), 7.20(s,1H), 7.25(dd,1H,J=2.0,8.4 Hz),
7.58(d,1H,J=8.8 Hz), 7.73(d,1H,J=2.0 Hz), 7.87(brd,2H,J=8.4 Hz),
7.94(brd,2H,J=8.4 Hz).
Synthetic Example 62
4-{2-[5-(4,7-Dimethylbenzofuran-2-yl)furyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.46(s,6H),
6.97(d,1H,J=7.6 Hz), 7.04(d,1H,J=7.6 Hz), 7.11(d,1H,J=4.0 Hz),
7.35(d,1H,J=4.0 Hz), 7.40(s,1H), 7.95(d,2H,J=8.4 Hz),
8.01(d,2H,J=8.4 Hz).
Synthetic Example 63
4-{2-[5-(4,7-Dimethylbenzofuran-2-yl)thienyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.42(s,6H),
6.96(d,1H,J=7.2 Hz), 7.02(d,1H,J=7.2 Hz), 7.38(s,1H),
7.68(d,1H,J=4.0 Hz), 7.76(d,1H,J=4.0 Hz), 7.85(d,2H,J=7.6 Hz),
7.98(d,2H,J=7.6 Hz).
Synthetic Example 64
4-{2-[5-(4,7-Dichlorobenzofuran-2-yl)furyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 7.30(d,1H,J=3.6 Hz),
7.38-7.42(m,2H), 7.47(d,1H,J=8.0 Hz), 7.52(s,1H),
7.97-8.03(m,4H).
Synthetic Example 65
4-{2-[5-(4,7-Dichlorobenzofuran-2-yl)thienyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 7.39(d,1H,J=8.0 Hz),
7.45(d,1H,J=8.0 Hz), 7.55(s,1H), 7.80(d,1H,J=4.4 Hz),
7.84-7.90(m,3H), 7.98(d,2H,J=8.4 Hz).
Synthetic Example 66
5-{2-[5-(4,7-Dimethylbenzofuran-2-yl)pyrrolyl]}thiophene-2-carboxylic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.43(s,3H),
2.45(s,3H), 6.62-6.65(m,1H), 6.66-6.69(m,1H), 6.92(d,1H,J=7.6 Hz),
6.96(d,1H,J=7.6 Hz), 7.19(s,1H), 7.45(d,1H,J=3.6 Hz),
7.67(d,1H,J=3.6 Hz), 11.96(brs,1H), 12.97(brs,1H).
Synthetic Example 67
4-{2-[5-(2,3,4,7-Tetramethylbenzofuran-5-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.28(s,3H),
2.35(s,3H), 2.37(s,3H), 2.57(s,3H), 6.16(brs,1H), 6.75(brs,1H),
7.06(s,1H), 7.80(d,2H,J=8.4 Hz), 7.86(d,2H,J=8.4 Hz),
11.36(brs,1H), 12.69(brs,1H).
Synthetic Example 68
4-{2-[5-(2,3-Dimethylbenzofuran-5-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.18(s,3H),
2.35(s,3H), 6.59(brs,1H), 6.73(brs,1H), 7.42(d,1H,J=8.2 Hz),
7.61(dd,1H,J=2.0,8.2 Hz), 7.82-7.94(m,5H), 11.36(brs,1H),
12.76(brs,1H).
Synthetic Example 69
4-{2-[5-(7-Chlorobenzothiophene-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 6.65-6.68(m,1H),
6.80-6.83(m,1H), 7.38-7.42(m,2H), 7.76-7.82(m,1H), 7.80(s,1H),
7.89(d,2H,J=8.4 Hz), 7.94(d,2H,J=8.4 Hz), 11.87(s,1H),
12.82(brs,1H).
Synthetic Example 70
4-{2-[5-(5,7-Dimethylbenzothiophene-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.36(s,3H),
2.42(s,3H), 6.54-6.56(m,1H), 6.77-6.79(m,1H), 6.96(s,1H),
7.43(s,1H), 7.71(s,1H), 7.88(d,2H,J=8.4 Hz), 7.93(d,2H,J=8.4 Hz),
11.76(s,1H), 12.76(brs,1H).
Synthetic Example 71
4-{2-[5-(7-n-Propylbenzothiophene-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 0.96(t,3H,J=7.2 Hz),
1.75(sect,2H,J=7.2 Hz), 2.78(t,2H,J=7.2 Hz), 6.56-6.59(m,1H),
6.78-6.81(m,1H), 7.13(d,1H,J=7.2 Hz), 7.30(t,1H,J=7.2 Hz),
7.63(d,1H,J=7.2 Hz), 7.78(s,1H), 7.89(d,2H,J=8.4 Hz),
7.93(d,2H,J=8.4 Hz), 11.77(s,1H), 12.78(brs,1H).
Synthetic Example 72
4-{2-[5-(5-Fluoro-7-methylbenzothiophene-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 3.32(s,3H),
6.59-6.62(m,1H), 6.79-6.82(m,1H), 7.05(dd,1H,J=2.4, 9.0 Hz),
7.48(dd,1H,J=2.4, 9.0 Hz), 7.77(s,1H), 7.89(d,2H,J=8.4 Hz),
7.94(d,2H,J=8.4 Hz), 11.85(s,1H), 12.78(brs,1H).
Synthetic Example 73
4-{2-[5-(5-Chloro-7-methylbenzothiophene-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 3.30(s,3H),
6.60-6.62(m,1H), 6.79-6.82(m,1H), 7.19(d,1H,J=1.6 Hz),
7.73(d,1H,J=1.6 Hz), 7.75(s,1H), 7.88(d,2H,J=8.4 Hz),
7.94(d,2H,J=8.4 Hz), 11.86(s,1H), 12.80(brs,1H).
Synthetic Example 74
5-{2-[5-(7-Ethylbenzothiophene-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.32(t,3H,J=7.6 Hz),
2.82(q,2H,J=7.6 Hz), 6.57-6.59(m,1H), 6.78-6.81(m,1H),
7.15(d,1H,J=7.6 Hz), 7.31(t,1H,J=7.6 Hz), 7.64(d,1H,J=7.6 Hz),
7.79(s,1H), 7.89(d,2H,J=8.4 Hz), 7.94(d,2H,J=8.4 Hz), 11.78(s,1H),
12.83(brs,1H).
Synthetic Example 75
4-{2-[5-(7-Chloro-4-methylbenzothiophene-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.56(s,3H),
6.65-6.67(m,1H), 6.80-6.83(m,1H), 7.20(d,1H,J=7.6 Hz),
7.29(d,1H,J=7.6 Hz), 7.89(d,2H,J=8.4 Hz), 7.93(s,1H),
7.95(d,2H,J=8.4 Hz), 11.83(s,1H), 12.82(brs,1H).
Synthetic Example 76
4-{2-[5-(7-Isopropylbenzothiophene-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.33(d,6H,J=7.6 Hz),
3.10(quint,1H,J=7.6 Hz), 6.56-6.59(m,1H), 6.78-6.81(m,1H),
7.20(d,1H,J=7.6 Hz), 7.33(t,1H,J=7.6 Hz), 7.63(d,1H,J=7.6 Hz),
7.78(s,1H), 7.89(d,2H,J=8.4 Hz), 7.94(d,2H,J=8.4 Hz), 11.78(s,1H)
12.82(brs,1H).
Synthetic Example 77
4-{2-[5-(4,7-Dimethylbenzothiophene-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.42(s,3H),
2.54(s,3H), 6.56-6.59(m,1H), 6.78-6.81(m,1H), 7.02(d,1H,J=6.8 Hz),
7.08(d,1H,J=6.8 Hz), 7.89(s,1H), 7.90(d,2H,J=8.4 Hz),
7.94(d,2H,J=8.4 Hz), 11.76(s,1H), 12.83(brs,1H).
Synthetic Example 78
4-{2-[5-(4,7-Dichlorobenzothiophene-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 6.73-6.76(m,1H),
6.82-6.85(m,1H), 7.41(d,1H,J=8.0 Hz), 7.49(d,1H,J=8.0 Hz),
7.91(d,2H,J=8.4 Hz), 7.96(d,2H,J=8.4 Hz), 7.98(s,1H) 11.98(s,1H),
12.86(brs,1H).
Synthetic Example 79
4-{2-[5-(3,4,7-Trimethylbenzothiophene-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.40(s,3H),
2.66(s,3H), 2.72(s,3H), 6.38-6.41(m,1H), 6.79-6.82(m,1H),
6.94-7.10(m,2H), 7.78-7.96(m,4H), 11.65(s,1H).
Synthetic Example 80
4-{2-[5-(8-Methoxymethylnaphthalene-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 3.41(s,3H),
4.97(s,2H), 6.81(m,1H), 6.83(m,1H), 7.40(t,1H,J=7.6 Hz),
7.50(d,1H,J=6.8 Hz), 7.81(d,1H,J=8.0 Hz), 7.90-7.97(m,6H),
8.34(s,1H), 11.63(s,1H), 12.83(brs,1H).
Synthetic Example 81
4-{2-[5-(8-Ethoxynaphthalene-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.51(t,3H,J=6.8 Hz),
4.26(q,2H,J=6.8 Hz), 6.73(m,1H), 6.83(m,1H), 6.95(d,1H,J=7.6 Hz),
7.34(t,1H,J=8.0 Hz), 7.41(d,1H,J=8.0 Hz), 7.86(d,1H,J=8.8 Hz),
7.92-7.95(m,5H), 8.48(s,1H), 11.70(s,1H).
Synthetic Eample 82
4-{2-[5-(8-Isopropoxynaphthalene-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.43(d,6H,J=6.0 Hz),
4.82(quint,1H,J=6.0 Hz), 6.71(m,1H), 6.82(m,1H), 7.33(t,1H,J=8.0
Hz), 7.39(d,1H,J=7.6 Hz), 7.85(d,1H,J=8.8 Hz), 7.93(m,5H),
8.44(s,1H), 11.70(s,1H).
Synthetic Example 83
4-{2-[5-(8-Methoxynaphthalene-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 4.01(s,3H),
6.76(m,1H), 6.82(m,1H), 6.97(d,1H,J=7.6 Hz), 7.36(t,1H,J=8.0 Hz),
7.42(d,1H,J=8.0 Hz), 7.85(d,1H,J=8.8 Hz), 7.90-7.96(m,5H),
8.55(s,1H), 11.69(s,1H).
Synthetic Example 84
4-{2-[5-(8-(2-Furyl)naphthalene-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 6.72(dd,1H,J=2.0,3.6
Hz), 6.75(dd,1H,J=1.6,3.2 Hz), 6.83(dd,1H,J=2.0,3.6 Hz),
7.05(d,1H,J=3.2 Hz), 7.50(t,1H,J=8.0 Hz), 7.74(dd,1H,J=1.2,7.2 Hz),
7.88-7.94(m,5H), 8.01(s,2H), 8.62(s,1H), 11.70(s,1H).
Synthetic Example 85
4-{2-[5-(7-Hydroxy-8-isopropenylnaphthalene-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.10(s,3H),
4.89(m,1H), 5.49(m,1H), 6.61(dd,1H,J=2.4,4.0 Hz),
6.79(dd,1H,J=2.4,3.6 Hz), 7.09(dd,1H,J=2.0,8.4 Hz), 7.64(d,1H,J=9.2
Hz), 7.71(d,1H,J=8.8 Hz), 7.89(d,2H,J=8.4 Hz), 7.92(d,2H,J=8.4 Hz),
8.01(s,1H), 9.40(s,1H), 11.66(s,1H).
Synthetic Example 86
4-{2-[5-(8-(1-Methoxyethyl)naphthalene-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.50(d,3H,J=6.0 Hz),
3.24(s,3H), 5.32(q,1H,J=6.4 Hz), 6.82(s,2H), 7.45(t,1H,J=7.6 Hz),
7.53(d,1H,J=6.8 Hz), 7.78(d,1H,J=7.6 Hz), 7.89-7.97(m,6H),
8.41(s,1H), 11.58(s,1H).
Synthetic Example 87
4-{2-[5-(8-(2-Thienyl)naphthalene-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 6.62(m,1H),
6.81(m,1H), 7.29(m,1H), 7.45(m,1H), 7.49(t,1H,J=7.6 Hz),
7.57(d,1H,J=7.2 Hz), 7.73(m,1H), 7.85-7.94(m,5H), 8.03(s,2H),
8.47(s,1H), 11.66(s,1H).
Synthetic Example 88
4-{2-[5-(5-Methoxy-8-isopropenylnaphthalene-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.20(s,3H),
3.96(s,3H), 5.04(s,1H), 5.42(s,1H), 6.70(m,1H), 6.81(m,1H),
6.87(d,1H,J=8.0 Hz), 7.24(d,1H,J=8.0 Hz), 7.88-7.96(m,5H),
8.19(m,2H), 11.66(s,1H).
Synthetic Example 89
4-{2-[5-(5-Methoxy-8-isopropylnaphthalene-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.33(d,6H,J=6.8 Hz),
3.85(quint,1H,J=6.8 Hz), 3.93(s,3H), 6.82(s,2H), 6.86(d,1H,J=8.0
Hz), 7.32(d,1H, LJ=8.0 Hz), 7.86-7.96(m,5H), 8.16(d,1H,J=8.4 Hz),
8.41(s,1H), 11.62(s,1H).
Synthetic Example 90
4-{2-[5-(5-Methoxy-8-ehtylnaphthalene-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.31(t,3H,J=7.2 Hz),
3.09(q,2H,J=7.2 Hz), 3.93(s,3H), 6.80-6.84(m,3H), 7.25(d,1H,J=8.0
Hz), 7.88-7.96(m,5H), 8.15(d,1H,J=8.8 Hz), 8.33(s,1H).
Synthetic Example 91
4-{2-[5-(5-Methoxy-8-methylnaphthalene-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.63(s,3H),
3.92(s,3H), 6.77-6.82(m,3H), 7.24(d,1H,J=8.0 Hz), 7.86-7.95(m,5H),
8.13(d,1H,J=8.8 Hz), 8.28(s,1H), 11.62(s,1H).
Synthetic Example 92
4-{2-[5-(7-Chloro-5-methoxybenzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 3.80(s,3H),
6.72-6.75(m,1H), 6.84-6.86(m,1H), 6.95(d,1H,J=2.0 Hz),
7.18(d,1H,J=2.4 Hz), 7.22(s,1H), 7.89(d,2H,J=8.4 Hz),
7.95(d,2H,J=8.4 Hz), 11.94(brs,1H).
Synthetic Example 93
4-{2-[5-(7-Chloro-5-methylbenzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.37(s,3H),
6.71-6.75(m,1H), 6.83-6.87(m,1H), 7.17(d,1H,J=0.4 Hz), 7.21(s,1H),
7.40(d,1H,J=0.4 Hz), 7.89(d,2H,J=8.4 Hz), 7.95(d,2H,J=8.8 Hz),
11.93(brs,1H).
Synthetic Example 94
4-{2-[5-(7-Chloro-5-ethylbenzofuran-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.22(d,3H,J=7.5 Hz),
2.67(q,2H,J=7.5 Hz), 6.73(dd,1H,J=2.4,3.6 Hz), 6.85(dd,1H,J=2.8,
3.2 Hz), 7.18-7.19(m,1H), 7.23(s,1H), 7.43-7.44(m,1H),
7.89(d,2H,J=8.4 Hz), 7.95(d,2H,J=8.8 Hz), 11.93(brs,1H).
Synthetic Example 95
4-{2-[5-(7-Chloro-4,5-dimethylbenzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.29(s,3H),
2.36(s,3H), 6.70-6.74(m,1H), 6.82-6.86(m,1H), 7.15(s,1H),
7.31(s,1H), 7.89(d,2H,J=7.6 Hz), 7.95(d,2H,J=7.6 Hz),
11.91(brs,1H).
Synthetic Example 96
4-{2-[5-(5-Ethyl-7-methylbenzofuran-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.21(t,3H,J=7.6 Hz),
6.63(q,2H,J=7.6 Hz), 6.67-6.72(m,1H), 6.80-6.85(m,1H),
6.88-6.93(m,1H), 7.12(s,1H), 7.22-7.26(m,1H), 7.88(d,2H,J=8.4 Hz),
7.94(d,2H,J=8.4 Hz), 11.80(brs,1H).
Synthetic Example 97
4-{2-[5-(7-Chloro-5-isopropenylbenzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.16(s,3H),
5.13-5.14(m,1H), 5.47-5.48(m,1H), 6.74-6.78(m,1H), 6.84-6.88(m,1H),
7.28(s,1H), 7.47(d,1H,J=1.6 Hz), 7.73(d,1H,J=1.6 Hz),
7.90(d,2H,J=8.4 Hz), 7.95(d,2H,J=8.8 Hz), 11.97(brs,1H).
Synthetic Example 98
4-{2-[5-(5,7-Dichloro-3-methylbenzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.35(s,3H),
6.66-6.70(m,1H), 6.80-6.84(m,1H), 7.45-7.49(m,1H), 7.68-7.72(m,1H),
7.80-7.90(m,4H), 11.84(brs,1H).
Synthetic Example 99
4-{2-[5-(7-Chloro-4-ethylbenzofuran-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.28(t,3H,J=7.6 Hz),
2.83(q,2H,J=7.6 Hz), 6.74-6.76(m,1H), 6.84-6.87(m,2H),
7.07(d,1H,J=8.0 Hz), 7.25(d,1H,J=8.0 Hz), 7.37(s,1H),
7.90(d,2H,J=8.4 Hz), 7.95(d,2H,J=8.4 Hz), 11.91(brs,1H).
synthetic Example 100
4-{2-[5-(4,5,7-Trimethylbenzofuran-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.26(s,3H),
2.35(s,3H), 2.43(s,3H), 6.67-6.71(m,1H), 6.81-6.85(m,1H),
6.87(s,1H), 7.21(s,1H), 7.88(d,2H,J=8.4 Hz), 7.94(d,2H,J=8.0 Hz),
11.78(brs,1H).
Synthetic Example 101
4-{2-[5-(6-Chloro-7-n-propylbenzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 0.96(t,3H,J=7.6 Hz),
1.64-1.76(m,2H), 2.95-3.03(m,2H), 6.73-6.76(m,1H), 6.83-6.87(m,1H),
7.19(s,1H), 7.26(d,1H,J=8.8 Hz), 7.47(d,1H,J=8.8 Hz),
7.89(d,2H,J=8.0 Hz), 7.96(d,2H,J=8.4 Hz), 11.87(brs,1H).
Synthetic Example 102
4-{2-[5-(4-Chloro-7-n-butylbenzofuran-2yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 0.92(t,3H,J=7.6 Hz),
1.29-1.38(m,2H), 1.64-1.74(m,2H), 2.84-2.92(m,2H), 6.75-6.79(m,1H),
6.83-6.87(m,2H), 7.08(d,1H,J=7.7 Hz), 7.22(d,1H,J=7.7 Hz),
7.28(s,1H), 7.88(d,2H,J=8.8 Hz), 7.96(d,2H,J=8.8 Hz),
11.90(brs,1H).
Synthetic Example 103
4-{2-[5-(3,5-Dichloro-4,7-dimethylbenzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.53(s,3H),
2.69(s,3H), 6.93(dd,1H,J=2.4, 4.0 Hz), 7.01(dd,1H,J=2.4, 4.0 Hz),
7.27(s,1H), 7.95(s,4H), 11.94(brs,1H).
Synthetic Example 104
4-{2-[5-(3-Chloro-4,7-dimethylbenzofuran-2-yl)pyrrolyl]}benzoic
acid
(A) Methyl
4-{2-[5-(3-chloro-4,7-dimethylbenzofuran-2-yl)pyrrolyl]}benzoate
0.30 g of methyl
4-{2-[5-(4,7-dimethylbenzofuran-2-yl)pyrrolyl]}benzoate was
dissolved in 10 ml N,N-dimethylformamide, then 0.13 g of
N-chlorosuccinimide was added thereto, and the mixture was stirred
at room temperature for 14 hours. 30 ml ethyl acetate was added to
the reaction solution, and the organic layer was washed with brine
and then dried over anhydrous magnesium sulfate. After the drying
agent was filtered off, the filtrate was concentrated and the
resulting crude product was purified by silica gel column
chromatography. The resulting solid was washed with methanol to
give 0.12 g of the title compound as pale yellow crystals.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 2.50(s,3H), 2.71(s,3H),
3.92(s,3H), 6.77-6.80(m,1H), 6.91(d,1H,J=7.6 Hz), 6.98(d,1H,J=7.6
Hz), 7.01-7.04(m,1H), 7.63(d,2H,J=8.4 Hz), 8.08(d,2H,J=8.4 Hz),
9.23(brs,1H).
(B) 4-{2-[5-(3-Chloro-4,7-dimethylbenzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1 (D).
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.52(s,3H),
2.65(s,3H), 6.90-6.93(m,1H), 6.95-6.99(m,2H), 7.04-7.08(m,1H),
7.95(s,4H), 11.89(brs,1H).
Synthetic Example 105
4-{2-[5-(4,7-Diethylbenzofuran-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.27(t,3H,J=7.6 Hz),
1.30(t,3H,J=7.6 Hz), 2.81(q,2H,J=7.6 Hz), 2.88(q,2H,J=7.6 Hz),
6.70(dd,1H,J=2.4,4.0 Hz), 6.83(dd,1H,J=2.8, 3.6 Hz),
6.96(d,1H,J=7.6 Hz), 7.01(d,1H,J=7.6 Hz), 7.27(s,1H),
7.88(d,2H,J=8.4 Hz), 7.94(d,2H,J=8.8 Hz), 11.78(brs,1H).
Synthetic Example 106
4-{2-[5-(5-Chloro-7-fluorobenzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 6.75-6.84(m,2H),
7.25(s,1H), 7.33(dd,1H,J=2.4,8.8 Hz), 7.60(d,1H,J=2.4 Hz),
7.85(d,2H,J=8.4 Hz), 7.94(d,2H,J=8.4 Hz), 12.00(s,1H).
Synthetic Example 107
4-{2-[5-(7-Ethynylbenzofuran-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 4.55(s,1H),
6.73(dd,1H,J=2.4, 4.0 Hz), 6.85(dd,1H,J=2.4,4.0 Hz),
7.23(t,1H,J=8.0 Hz), 7.26(s,1H), 7.36(dd,1H,J=4.2,8.0 Hz),
7.69(dd,1H,J=1.2, 8.0 Hz), 7.89(d,2H,J=8.4 Hz), 7.95(d,2H,J=8.4
Hz), 11.94(brs,1H).
Synthetic Example 108
4-{2-[5-(7-(2-Methoxyethyl)benzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 3.14(t,2H,J=7.2 Hz),
3.27(s,3H), 3.70(t,2H,J=7.2 Hz), 6.73(dd,1H,J=2.4,3.6 Hz),
6.84(dd,1H,J=2.4,3.6 Hz), 7.11-7.16(m,2H), 7.18(s,1H),
7.46(dd,1H,J=2.0,6.8 Hz), 7.89(d,2H,J=8.4 Hz), 7.94(d,2H,J=8.4 Hz),
11.85(s,1H), 12.83(brs,1H).
Synthetic Example 109
4-{2-[5-(5-Fluoro-7-methylbenzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.43(s,3H),
6.75(brs,1H), 6.85(brs,1H), 6.93(d,1H,J=10.0 Hz), 7.19(s,1H),
7.26(d,1H,J=6.8 Hz), 7.89(d,2H,J=8.0 Hz), 7.95(d,2H,J=8.0 Hz),
11.90(s,1H).
Synthetic Example 110
4-{2-[5-(4-Fluoro-7-methylbenzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.42(s,3H),
6.72(brs,1H), 6.84(brs,1H), 7.06(t,1H,J=8.0 Hz), 7.19(s,1H),
7.44(dd,1H,J=6.0,8.0 Hz), 7.88(d,2H,J=8.0 Hz), 7.94(d,2H,J=8.0 Hz),
11.85(brs,1H).
Synthetic Example 111
4-{2-[5-(7-Bromo-4-fluorobenzofuran-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 6.78(dd,1H,J=2.4,3.6
Hz), 6.87(dd,1H,J=2.4,3.6 Hz), 7.09(t,1H,J=9.2 Hz),
7.48(dd,1H,J=4.8,8.4 Hz), 7.49(s,1H), 7.93(d,2H,J=8.8 Hz),
7.96(d,2H,J=8.8 Hz), 12.20(brs,1H).
Synthetic Example 112
2-{2-[5-(4,7-Dimethylbenzofuran-2-yl)pyrrolyl]}pyridine-5-carboxylic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.44(s,3H),
2.46(s,3H), 6.72-6.76(m,1H), 6.92(d,1H,J=8.0 Hz), 6.96(d,1H,J=8.0
Hz), 7.04-7.09(m,1H), 7.51(s,1H), 7.93(d,1H,J=7.6 Hz),
8.20(dd,1H,J=2.4,7.6 Hz), 9.02(d,1H,J=2.4 Hz), 12.26(brs,1H).
Synthetic Example 113
4-{2-[5-(4,6,7-Trimethylbenzofuran-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.29(s,3H),
2.38(s,3H) 2.40(s,3H), 6.69(brs,1H), 6.81-6.84(m,2H), 7.17(s,1H),
7.86-7.95(m,4H), 11.76((brs,1H), 12.82(brs,1H).
Synthetic Example 114
6-{2-[5-(4,7-Dimethylbenzofuran-2-yl)pyrrolyl]}-2-naphthoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.46(s,3H),
2.47(s,3H), 6.73(brd,1H,J=3.6 Hz), 6.90(brd,1H,J=3.7 Hz),
6.92(d,1H,J=6.8 Hz), 6.96(d,1H,J=6.8 Hz), 7.25(s,1H),
7.93(d,1H,J=8.4 Hz), 7.97(d,1H,J=8.4 Hz), 8.01(d,1H,J=8.4 Hz),
8.10(d,1H,J=8.8 Hz), 8.35(s,1H), 8.53(s,1H), 11.88(brs,1H).
Synthetic Example 115
4-{2-[5-(4,7-Dimethylbenzofuran-2-yl)pyrrolyl]}-1-naphthoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.41(s,3H),
2.47(s,3H), 6.58(t,1H,J=3.0 Hz), 6.81(t,1H,J=3.0 Hz), 6.93(ABq,
2H,J=9.0 Hz), 7.18(s,1H), 7.58-7.70(m,2H), 7.72(d,1H,J=9.0 Hz),
8.17(d,1H,J=9.0 Hz), 8.40(d,1H,J=9.0 Hz), 8.77(d,1H,J=9.0 Hz).
Synthetic Example 116
2,5-Dimethyl-4-{2-[5-(4,7-dimethylbenzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.41(s,3H),
2.42(s,3H), 2.47(s,3H), 2.55(s,3H), 6.48(dd,1H,J=2.5, 3.0 Hz),
6.71(dd,1H,J=2.5,3.0 Hz), 6.92(ABq, 2H,J=7.0 Hz), 7.18(s,1H),
7.46(brs,1H), 7.75(brs,1H).
Synthetic Example 117
5-{2-[5-(4,7-Dimethylbenzofuran-2-yl)pyrrolyl]}-2-furancarboxylic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.43(s,3H),
2.45(s,3H), 6.58(d,1H,J=3.6 Hz), 6.79(d,1H,J=3.6 Hz),
6.87-6.96(m,3H), 7.01-7.08(brs,1H), 7.18(s,1H).
Synthetic Example 118
3-{2-[5-(4,7-Dimethylbenzofuran-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.49(s,3H),
2.57(s,3H), 6.70(dd,1H,J=2.5,3.8 Hz), 6.74(dd,1H,J=2.5,3.8 Hz),
6.83(s,1H), 6.93(d,1H,J=7.5 Hz), 6.97(d,1H,J=7.5 Hz),
7.52(t,1H,J=8.0 Hz), 7.83(d,1H,J=7.5 Hz), 7.96(d,1H,J=7.5 Hz),
8.28(s,1H), 9.03(brs,1H).
Synthetic Example 119
3-Bromo-4-{2-[5-(naphtho[1,2-b]furan-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 6.86(m,2H),
7.31(s,1H), 7.51(t,1H,J=7.6 Hz), 7.65(t,1H,J=7.8 Hz), 7.75(s,1H),
7.79(d,1H,J=8.0 Hz), 7.99(dd,1H,J=1.2,8.4 Hz), 8.02(d,1H,J=8.4 Hz),
8.19(s,1H), 8.32(d,1H,J=8.0 Hz), 11.98(brs,1H).
Synthetic Example 120
3-Bromo-4-{2-[5-(4,7-dichlorobenzofuran-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 6.80(d,1H,J=3.6 Hz),
6.83(d,1H,J=3.6 Hz), 7.34(dd,1H,J=1.0,8.2 Hz), 7.35(s,1H),
7.37(dd,1H,J=0.6,8.6 Hz), 7.70(brd,1H,J=8.4 Hz), 7.94(brd,1H,J=8.0
Hz), 8.16(brs,1H).
Synthetic Example 121
4-{2-[5-(3,4-Dimethylnaphthalene-1-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.54(s,3H),
2.65(s,3H), 6.57(dd,1H,J=2.8,2.8 Hz), 6.85(dd,1H,J=3.2,3.2 Hz),
7.43(s,1H), 7.47(dd,1H,J=7.6,7.6 Hz), 7.55(dd,1H,J=7.2,7.2 Hz),
7.62(d,1H,J=8.4 Hz), 8.11(d,4H,J=8.0 Hz), 8.68(brs,1H).
Synthetic Example 122
4-{2-[5-(5,8-Dimethylnaphthalene-2-yl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.61(s,3H),
2.67(s,3H), 7.23(d,1H,J=7.2 Hz), 7.26(d,1H,J=7.6 Hz),
7.64(d,1H,J=4.0 Hz), 7.70(d,2H,J=8.0 Hz), 7.73(d,1H,J=3.6 Hz),
7.91(d,3H,J=8.4 Hz), 8.06(d,1H,J=8.8 Hz), 8.21(s,1H).
Synthetic Example 123
4-{2-[5-(5,8-Dimethylnaphthalene-2-yl)furyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.61(s,3H),
2.70(s,3H), 7.24(d,1H,J=6.8 Hz), 7.27(d,1H,J=7.2 Hz), 7.33(s,2H),
7.97(d,2H,J=8.4 Hz), 8.01(d,3H,J=8.4 Hz), 8.07(d,1H,J=8.8 Hz),
8.39(s,1H).
Synthetic Example 124
4-{2-[5-(8-Ethyl-1-methoxynaphthalene-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 1.36(t,3H,J=7.2 Hz),
3.35(q,2H,J=7.6 Hz), 3.74(s,3H), 6.77-6.81(m,2H), 7.30-7.40(m,2H),
7.60-7.73(m,5H), 8.10-8.20(m,2H), 10.34(brs,1H).
Synthetic Example 125
4-{2-[5-(8Methyl-1-methoxynaphthalene-2-yl)pyrrolyl]}benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 2.97(s,3H), 3.73(s,3H),
6.76-6.80(m,2H), 7.28-7.35(m,2H), 7.61-7.72(m,5H), 8.14(d,2H,J=8.4
Hz), 10.33(brs,1H).
Synthetic Example 126
4-{2-[5-(5-Acenaphthenyl)pyrrolyl]}benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 3.40-3.48(m,4H),
6.64-6.66(m,1H), 6.84-6.86(m,1H), 7.33-7.36(m,2H), 7.50-7.64(m,4H),
8.03(d,1H,J=8.4 Hz), 8.09-8.12(m,2H), 8.76(brs,1H).
Synthetic Example 127
4-{2-[5(5,8-Dimethyl-2H-chromen-3-yl)pyrrolyl}]benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.09(s,3H),
2.34(s,3H), 4.95(brs,2H), 6.45-6.47(m,1H), 6.67(d,1H,J=7.6 Hz),
6.75-6.77(m,1H), 6.84(d,1H,J=7.6 Hz), 7.24(brs,1H),
7.85-7.94(m,4H).
Synthetic Example 128
4-{2-[5-(5-Isopropyl-8-methyl-2H-chromen-3-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 1.30(d,6H,J =6.8 Hz),
3.28(hept.,1H,J=6.8 Hz), 4.99(d,2H,J=1. 2 Hz), 6.39-6.40(m,1H),
6.71-6.73(m,1H), 6.81-6.86(m,2H), 6.99(d,1H,J=8.0 Hz),
7.64(d,2H,J=8.4 Hz), 8.13(d,2H,J=8.4 Hz), 8.70(brs,1H).
Synthetic Example 129
4-{2-[5-(5-Methyl-2H-chromen-3-yl)pyrrolyl}]benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.14(s,3H),
5.04(brs,2H), 6.43-6.45(m,1H), 6.75-6.77(m,1H), 6.81(t,1H,J=7.6
Hz), 6.95(t,1H,J=8.0 Hz), 7.09(brs,1H), 7.86-7.93(m,4H),
11.39(s,1H), 12.82(brs,1H).
Synthetic Example 130
4-{2-[5-(5-Ethyl-2H-chromen-3-yl)pyrrolyl}]benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.13(t,3H,J=7.2 Hz),
2.48-2.55(m,2H), 5.02(brs,2H), 6.45(brs,1H), 6.75-7.09(m,5H),
7.85-7.93(m,4H), 11.39(s,1H), 12.81(s,1H).
Synthetic Example 131
4-{2-[5-(5-Methoxy-2H-chromen-3-yl)pyrrolyl}]benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 3.91(s,3H),
5.00(brs,2H), 6.34(brs,1H), 6.50-6.55(m,2H), 6.70(s,1H),
6.95(s,1H), 7.08(dd,1H,J=7.2,7.2HZ), 7.62(d,2H,J=7.6 Hz),
8.11(d,2H,J=8.4 Hz), 8.77(brs,1H).
Synthetic Example 132
4-{2-[5-(8-Methoxy-7-methyl-2H-chromen-3-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 2.16(s,3H), 3.73(s,3H),
5.01(brs,2H), 6.44(m,1H), 6.70-7.77(m,3H), 7.07(s,1H),
7.85-7.93(m,4H), 11.38(brs,1H), 12.80(brs,1H).
Synthetic Example 133
4-{2-[5-(4-Methyl-2H-chromen-6-yl)pyrrolyl}]benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 2.10(d,3H,J=1.6 Hz),
4.79(q,2H,J=1.6 Hz), 5.65(m,1H), 6.51(dd,1H,J=2.8,3.6 Hz),
6.74(dd,1H,J=2.8,3.6 Hz), 6.85(d,1H,J=8.0 Hz), 7.29-7.32(m,2H),
7.59(d.2H,J=8.8 Hz), 8.10(d,2H,J=8.4 Hz), 8.60(brs,1H).
Synthetic Example 134
4-{2-[5-(5-Bromo-8-methoxy-2H-chromen-3-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 3.75(s,3H),
4.97(brs,2H), 6.53(brs,1H), 6.79-6.82(m,2H), 7.14(d,1H,J=8.8 Hz),
7.22(brs,1H), 7.91(brs,4H), 11.65(brs,1H), 12.83(brs,1H).
Synthetic Example 135
4-{2-[5-(8-Methoxy-5-methyl-2H-chromen-3-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 2.37(s,3H), 3.88(s,3H),
5.05(brs,2H), 6.40(brs,1H), 6.71-6.72(m,4H), 7.64(d,2H,J=7.6 Hz),
8.12(d,2H,J=8.0 Hz), 8.68(brs,1H).
Synthetic Example 136
4-{2-[5-(5-Propyl-2H-chromen-3yl)pyrrolyl}]benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 0.97(t,3H,J=7.2 Hz),
1.63(tq, 2H,J=7.2,7.2 Hz), 2.59(t,2H,J=7.6 Hz), 5.04(s,2H),
6.36(dd,1H,J=2.4,2.4 Hz), 6.62(brs,1H), 6.86(dd,1H,J=7.6,7.6 Hz),
6.94-7.01(m,2H), 7.61(d,2H,J=8.4 Hz), 8.11(d,2H,J=8.4 Hz),
8.63(brs,1H).
Synthetic Example 137
4-{2-[5-(5-Chloro-8-methyl-2H-chromen-3-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 2.19(s,3H),
5.05(d,2H,J=1.2 Hz), 6.41(dd,1H,J=3.6,3.6 Hz), 6.71(dd,1H,J=3.6,3.6
Hz), 6.90(brs,3H), 7.64(d,2H,J=8.8 Hz), 8.11(d,1H,J=8.8 Hz),
8.74(brs,1H).
Synthetic Example 138
4-{2-[5-(5,7,8-Trimethyl-2H-chromen-3-yl)pyrrolyl}]benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.02(s,3H),
2.15(s,3H), 2.31(s,33H), 4.91(s,2H), 6.43(brs,1H), 6.60(s,1H),
6.75(brs,1H), 7.23(s,1H), 7.85-7.93(m,4H), 11.35(s,1H),
12.78(brs,1H).
Synthetic Example 139
4-{2-[5-(5,7-Dimethyl-2H-chromen-3-yl)pyrrolyl}]benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.19(s,3H),
2.34(s,3H), 4.90(s,2H), 6.43(dd,1H,J=3.2,3.2 Hz), 6.49(brs,1H),
6.60(brs,1H), 6.75(dd,1H,J=3.2,3.2 Hz), 7.23(brs,1H),
7.86(d,2H,J=8.4 Hz), 7.93(d,2H,J=8.8 Hz).
Synthetic Example 140
4-{2-[5-(7,8-Dimethyl-2H-chromen-3-yl)pyrrolyl}]benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.07(s,3H),
2.19(s,3H), 5.00(s,2H), 6.41-6.43(m,1H), 6.72-6.76(m,2H),
6.84(d,1H,J=7.6 Hz), 7.06(brs,1H), 7.86(d,2H,J=8.4 Hz),
7.91(d,2H,J=8.8 Hz).
Synthetic Example 141
4-{2-[5-(6-Methyl-2H-chromen-3-yl)pyrrolyl}]benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.22(s,3H),
4.97(s,2H), 6.44(dd,1H,J=2.0,2.0 Hz), 6.70(d,1H,J=7.6 Hz),
6.76(dd,1H,J=2.0,2.0 Hz), 6.87-6.89(m,2H), 7.06(s,1H),
7.85-7.93(m,4H), 11.39(s,1H), 12.79(brs,1H).
Synthetic Example 142
4-{2-[5-(5,6-Dimethyl-2H-chromen-3-yl)pyrrolyl}]benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.10(s,3H),
2.19(s,3H), 4.99(s,2H), 6.44(s,1H), 6.73(s,1H), 6.77(brs,2H),
7.04(s,1H), 7.86-7.93(m,4H), 11.38(s,1H), 12.78(brs,1H).
Synthetic Example 143
4-{2-[5-(6-Chloro-2H-chromen-3-yl)pyrrolyl}]benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 5.05(s,2H),
6.46-6.52(m,1H), 6.74-6.79(m,1H), 6.83(d,1H,J=8.8 Hz),
7.05-7.10(m,3H), 7.86(d,2H,J=8.4 Hz), 7.92(d,2H,J=8.0 Hz),
11.47(s,1H), 12.80(brs,1H).
Synthetic Example 144
4-{2-[5-(7-Chloro-2H-chromen-3-yl)pyrrolyl}]benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 5.06(s,2H),
6.47(dd,1H,J=2.4,3.2 Hz), 6.77(dd,1H,J=2.4,3.2 Hz), 6.91(d,1H,J=2.0
Hz), 6.96(dd,1H,J=2.0,8.0 Hz), 7.10(d,1H,J=8.0 Hz), 7.10(s,1H),
7.87(d,2H,J=8.4 Hz), 7.92(d,2H,J=8.8 Hz), 11.44(s,1H),
12.81(brs,1H).
Synthetic Example 145
4-{2-[5-(5,6,7-Trimethyl-2H-chromen-3-yl)pyrrolyl}]benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.08(s,2H),
2.18(s,3H), 2.31(s,3H), 4.83(s,2H), 6.43(dd,1H,J=2.8,2.8 Hz),
6.53(s,1H), 6.75(dd,1H,J=3.2,3.2 Hz), 7.86(d,2H,J=8.4 Hz),
7.93(d,2H,J=8.0 Hz), 11.36(s,1H), 12.78(brs,1H).
Synthetic Example 146
4-{2-[5-(5,6,8-Trimethyl-2H-chromen-3-yl)pyrrolyl}]benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.07(s,3H),
2.14(s,3H), 2.26(s,3H), 4.88(s,2H), 6.46(dd,1H,J=2.4,2.4 Hz),
6.75-6.77(m,2H), 7.33(s,1H), 7.87(d,2H,J=8.8 Hz), 7.93(d,2H,J=8.4
Hz), 11.39(s,1H), 12.78(brs,1H).
Synthetic Example 147
4-{2-[5-(5-Chloro-2H-chromen-3-yl)pyrrolyl}]benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 5.04(brs,2H),
6.54(dd,1H,J=2.8,2.8 Hz), 6.29(dd,1H,J-2.8,2.8 Hz), 6.82(d,1H,J=8.4
Hz), 7.02-7.10(m,2H), 7.37(brs,1H), 7.90-7.95(m,4H), 11.63(s,1H),
12.81(brs,1H).
Synthetic Example 148
4-{2-[5-(8-Methyl-2H-chromen-3-yl)pyrrolyl}]benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 2.13(brs,2H),
5.03(brs,2H), 6.43-6.45(m,1H), 6.75-6.77(m,1H), 6.81(dd,1H,J=7.2,
7.2 Hz), 6.92-6.96(m,2H), 7.08(brs,1H), 7.85-7.93(m,4H).
Synthetic Example 149
4-{2-[5-(8-Trifluoromethyl-2H-chromen-3-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 5.17(s,2H),
6.53(brs,1H), 6.79(brs,1H), 7.07(dd,1H,J=7.6, 7.6 Hz), 7.16(s,1H),
7.36-7.38(m,2H), 7.86-7.94(m,4H), 11.49(s,1H), 12.80(brs,1H).
Synthetic Example 150
4-{2-[5-(3-Fluoro-4,7-dimethylbenzofuran-2-yl)pyrrolyl}]benzoic
acid
(A) Methyl
4-{2-[5-(3-fluoro-4,7-dimethylbenzofuran-2-yl)pyrrolyl}]benzoate
0.20 g of methyl
4-{2-[5-(4,7-dimethylbenzofuran-2-yl)pyrrolyl]}benzoate was
dissolved in 5 ml anhydrous tetrahydrofuran, then 0.20 g of
N-fluoro-3,5-dichloropyridinium triflate was added thereto, and the
mixture was stirred at room temperature for 30 minutes. The
reaction solution was poured into a cold aqueous saturated sodium
bicarbonate solution, 50 ml ethyl acetate was added thereto, and
the organic layer was washed with brine and then dried over
anhydrous magnesium sulfate. After the drying agent was filtered
off, the filtrate was concentrated and the resulting crude product
was purified by silica gel column chromatography to give 0.05 g of
the title compound as pale yellow crystals.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 2.48(s,3H), 2.60(s,3H),
3.94(s,3H), 6.75-6.79(m,2H), 6.92(d,1H,J=7.6 Hz), 6.99(d,1H,J=7.6
Hz), 7.62(d,2H,J=8.4 Hz), 8.07(d,2H,J=8.4 Hz), 8.92(brs,1H).
(B) 4-{2-[5-(3-Fluoro-4,7-dimethylbenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1 (D).
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.45(s,3H),
2.53(s,3H), 6.63-6.66(m,1H), 6.89-6.92(m,1H), 6.98(d,1H,J=7.2 Hz),
7.06(d,1H,J=7.2 Hz), 7.93(s,4H), 11.87(s,1H), 12.83(brs,1H).
Synthetic Example 151
4-{2-[5-(3-Bromo-4,7-dimethylbenzofuran-2-yl)pyrrolyl}]benzoic
acid
(A) Methyl
4-{2-[5-(3-bromo-4,7-dimethylbenzofuran-2-yl)pyrrolyl}]benzoate
The title compound was produced in the same manner as for the
3-chloro compound by use of N-bromosuccinimide in place of
N-chlorosuccinimide.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 2.50(s,3H), 2.73(s,3H),
3.93(s,3H), 6.77-6.80(m,1H), 6.91(d,1H,J=7.6 Hz), 6.98(d,1H,J=7.6
Hz), 7.11-7.14(m,1H), 7.63(d,2H,J=8.4 Hz), 8.08(d,2H,J=8.4 Hz),
9.38(brs,1H).
(B) 4-{2-[5-(3-Bromo-4,7-dimethylbenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1 (D).
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.50(s,3H),
2.67(s,3H), 6.88-6.91(m,1H), 6.96(d,1H,J=7.2 Hz), 7.03-7.07(m,2H),
7.92(s,4H), 11.86(s,1H), 12.83(brs,1H).
Synthetic Example 152
4-{2-[5-(6,7-Dichlorobenzofuran-2-yl)pyrrolyl}]benzoic acid
The title compound was obtained in the same manner.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 6.76-6.79(m,1H),
6.85-6.88(m,1H), 7.30(s,1H), 7.47(d,1H,J=8.4 Hz), 7.64(d,1H,J=8.4
Hz), 7.89(d,2H,J=8.4 Hz), 7.96(d,2H,J=8.4 Hz), 11.98(s,1H),
12.85(brs,1H).
Synthetic Example 153
4-{2-[5-(3-Chloro-5,7-dimethylbenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.37(s,3H),
2.51(s,3H), 6.90-6.97(m,2H), 7.02(brs,1H), 7.16(brs,1H),
7.94(s,4H), 11.91(s,1H), 12.85(brs,1H).
Synthetic Example 154
4-{2-[5-(3-Chloro-7-propylbenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 0.95(t,3H,J=7.6 Hz),
1.70-1.82(m,2H), 2.94(t,2H,J=7.6 Hz), 6.91-6.94(m,1H),
6.96-6.99(m,1H), 7.22(dd,1H,J=1.2,7.6 Hz), 7.29(t,1H,J=7.6 Hz),
7.38(dd,1H,J=1.2,7.6 Hz), 7.93(s,4H), ll.90(s,1H),
12.89(brs,1H).
Synthetic Example 155
4-{2-[5-(3-Fluoro-5,7-dimethylbenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.35(s,3H),
2.46(s,3H), 6.61-6.64(m,1H), 6.85-6.88(m,1H), 7.00(brs,1H),
7.22(brs,1H), 7.89(s,4H), 11.86(s,1H), 12.83(brs,1H).
Synthetic Example 156
4-{2-[5-(5-Fluoro-3,7-dimethylbenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.33(s,3H),
2.53(s,3H), 6.64-6.67(m,1H), 6.87-6.90(m,1H), 6.95(dd,1H,J=2.0,10.4
Hz), 7.22(dd,1H,J=2.0,10.4 Hz), 7.93(s,4H), 11.73(s,1H),
12.84(brs,1H).
Synthetic Example 157
4-{2-[5-(5-Fluoro-4,7-dimethylbenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.34(s,3H),
2.46(s,3H), 6.71-6.74(m,1H), 6.83-6.86(m,1H), 6.90(d,1H,J=10.8 Hz),
7.26(s,1H), 7.89(d,2H,J=8.4 Hz), 7.95(d,2H,J=8.4 Hz), 11.84(s,1H),
12.83(brs,1H).
Synthetic Example 158
4-{2-[5-(5-Fluoro-3,4,7-Trimethylbenzofuran-2yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.48(s,6H),
2.50(s,3H), 6.59-6.62(m,1H), 6.85-6.88(m,1H), 6.92(d,1H,J=10.8 Hz),
7.92(s,4H), 11.72(s,1H), 12.80(brs,1H).
Synthetic Example 159
4-{2-[5-(3,5-Difluro-4,7-dimethylbenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.42(s,3H),
2.48(s,3H), 6.65-6.68(m,1H), 6.89-6.92(m,1H), 7.03(d,1H,J=10.8 Hz),
7.93(s,4H), 11.91(s,1H), 12.85(brs,1H).
Synthetic Example 160
4-{2-[5-(3-Chloro-5-fluoro-4,7-(dimethylbenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.48(s,3H),
2.52(s,3H), 6.91-6.94(m,1H), 6.98-7.01(m,1H), 7.04(d,1H,J=10.8 Hz),
7.95(s,4H), 11.92(s,1H), 12.86(brs,1H).
Synthetic Example 161
4-{2-[5-(7-Ethoxy-5-fluoro-4-methylbenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.38(t,3H,J=7.6 Hz),
2.29(s,3H), 4.20(q,2H,J=7.6 Hz), 6.69-6.72(m,1H), 6.77(d,1H,J=10.8
Hz), 6.81-6.84(m,1H), 7.26(s,1H), 7.89(d,2H,J=8.4 Hz),
7.94(d,2H,J=8.4 Hz), 11.88(s,1H), 12.80(brs,1H).
Synthetic Example 162
4-{2-[5-(7-Ethyl-5-fluoro-4-methylbenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.27(t,3H,J=7.6 Hz),
2.34(s,3H), 2.85(q,2H,J=7.6 Hz), 6.71-6.74(m,1H), 6.83-6.86(m,1H),
6.91(d,1H,J=10.8 Hz), 7.88(d,2H,J=8.4 Hz), 7.95(d,2H,J=8.4 Hz),
11.83(s,1H), 12.86(brs,1H).
Synthetic Example 163
4-{2-[5-(7-Ethyl-3,5-difluoro-4-methylbenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.28(t,3H,J=7.6 Hz),
2.43(s,3H) 2.90(q,2H,J=7.6 Hz), 6.65-6.68(m,1H), 6.86-6.89(m,1H),
7.04(d,1H,J=11.2 Hz), 7.85-7.96(m,4H), 11.87(s,1H),
12.85(brs,1H).
Synthetic Example 164
4-{2-[5-(7-Chloro-4-fluorobenzothiophene-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 6.71-6.74(m,1H),
6.81-6.84(m,1H), 7.27(t,1H,J=8.8 Hz), 7.42(dd,1H,J=4.4,8.8 Hz),
7.90(d,2H,J=8.4 Hz), 7.95(d,2H,J=8.4 Hz), 11.40(s,1H),
12.81(brs,1H).
Synthetic Example 165
4-{2-[5-(3,5-Dichloro-7-methylbenzothiophene-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.52(s,3H),
6.87-6.94(m,2H), 7.38(brs,1H), 7.61(brs,1H), 7.90(s,4H),
11.81(s,1H), 12.85(brs,1H).
Synthetic Example 166
4-{2-[5-(3-Chloro-5-fluoro-7-methylbenzothiophene-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.53(s,3H),
6.88-6.94(m,4H), 7.24(dd,1H,J=2.4,9.6 Hz), 7.40(dd,1H,J=2.4,9.6
Hz), 7.93(s,4H), 11.80(s,1H), 12.87(brs,1H).
Synthetic Example 167
4-{2-[5-(7-fluoro-4-trifluoromethylbenzofuran-2-yl)pyrrolyl}]benzoic
acid
The benzofuran site was synthesized in the same manner as in
Synthetic Example 27. The other was obtained in the same manner as
in Synthetic Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 6.87-6.92(m,2H),
7.35(dd,1H,J=10.0,10.4 Hz), 7.53(brs,1H), 7.62(dd,1H,J=3.6,8.8 Hz),
7.93(d,2H,J=8.8 Hz), 7.96(d,2H,J=8.8 Hz).
Synthetic Example 168
4-{2-[5-(3-Chloro-5-fluoro-7-methylbenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.57(s,3H),
6.91-6.94(m,1H), 6.96-7.02(m,1H), 7.09(dd,1H,J=2.7,11.0 Hz),
7.17(dd,1H,J=2.3,8.0 Hz), 7.95(brs,4H), 12.0(s,1H).
Synthetic Example 169
4-{2-[5-(3-Chloro-7-ethyl-5-fluorobenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.30(t,3H,J=8.0 Hz),
3.00(q,2H,J=7.2 Hz), 6.90-6.93(m,1H), 6.98-7.00(m,1H),
7.12(dd,1H,J=2.9,10.4 Hz), 7.18(dd,1H,J=2.4,8.8 Hz),
7.93(d,2H,J=8.0 Hz), 7.96(d,2H,J=8.0 Hz), 11.96(brs,1H).
Synthetic Example 170
4-{2-[5-(3-Chloro-5-fluoro-7-propylbenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 0.96(t,3H,J=6.8 Hz),
1.72-1.80(m,2H), 2.96(t,2H,J=7.2 Hz), 6.90-6.93(m,1H),
6.98-7.01(m,1H), 7.10(dd,1H,J=2.0,10.4 Hz), 7.18(dd,1H,J=2.0, 7.6
Hz), 7.92(d,2H,J=8.4 Hz), 7.96(d,2H,J=8.4 Hz), 11.88(brs,1H).
Synthetic Example 171
4-{2-[5-(3-Chloro-5-fluoro-7-propylbenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 0.94(t,3H,J=7.0 Hz),
1.73-1.80(m,2H), 2.90-2.98(m,2H), 7.01(d,1H,J=2.8 Hz),
7.13(dd,1H,J=2.6,10.4 Hz), 7.22(dd,1H,J=2.4,8.0 Hz),
7.88(d,2H,J=8.4 Hz), 8.05(d,2H,J=8.4 Hz).
Synthetic Example 172
4-{2-[5-(3-Bromo-5-fluoro-7-methylbenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.58(s,3H),
6.92-6.94(m,1H), 7.06-7.16(m,3H), 7.95(brs,4H), 12.00(s,1H).
Synthetic Example 173
4-{2-[5-(7-Ethyl-5-fluoro-3-methylbenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.31(t,3H,J=7.6 Hz),
2.33(s,3H), 2.97(q,2H,J=7.6 Hz), 6.64-6.66(m,1H), 6.86-6.89(m,1H),
6.97(dd,1H,J=2.4,10.0 Hz), 7.22(dd,1H,J=2.4,8.8 Hz),
7.91(d,2H,J=8.4 Hz), 7.93(d,2H,J=8.4 Hz), 11.73(s,1H),
12.82(brs,1H).
Synthetic Example 174
4-{2-[5-(3,5-Difluoro-7-ethylbenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.32(t,3H,J=7.6 Hz),
2.96(q,2H,J=7.6 Hz), 6.68-6.71(m,1H), 6.91(dd,1H,J=2.4,3.6 Hz),
7.10(dd,1H,J=2.4,10.4 Hz), 7.30(dd,1H,J=2.4,8.0 Hz), 7.94(brs,4H),
11.95(s,1H), 12.86(brs,1H).
Synthetic Example 175
4-{2-[5-(4-Ethyl-5-fluoro-7-methylbenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.23(t,3H,J=7.6 Hz),
2.46(s,3H), 2.79(q,4H,J=7.6 Hz), 6.72-6.75(m,1H), 6.84-6.86(m,1H),
6.90(d,1H,J=10.8 Hz), 7.30(s,1H), 7.89(d,2H,J=8.4 Hz),
7.95(d,2H,J=8.4 Hz), 11.84(brs,1H)
Synthetic Example 176
4-{2-[5-(4,7-Diethyl-3,5-difluorobenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.23(t,3H,J=7.2 Hz),
1.30(t,3H,J=7.2 Hz), 2.82-2.88(m,2H), 2.92(q,2H,J=7.2 Hz),
6.67-6.70(m,1H), 6.90-6.92(m,1H), 7.05(d,1H,J=11.2 Hz), 7.94(s,4H),
11.90(brs,1H).
Synthetic Example 177
4-{2-[5-(3-Bromo-4,7-diethyl-5-fluorobenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.22(t,3H,J=7.6 Hz),
1.30(t,3H,J=7.6 Hz), 2.97(q,2H,J=7.6 Hz), 3.03-3.10(m,2H),
6.90-6.92(m,1H), 7.07(d,1H,J=11.2 Hz), 7.09-7.12(m,1H),
7.93(d,2H,J=8.4 Hz), 7.96(d,2H,J=8.4 Hz), 11.90(brs,1H).
Synthetic Example 178
4-{2-[5-(3,5-Dichloro-7-methylbenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.58(s,3H),
6.92-6.95(m,1H), 7.00-7.02(m,1H), 7.27-7.29(m,1H), 7.40-7.42(m,1H),
7.96(s,4H), 12.00(s,1H).
Synthetic Example 179
4-{2-[5-(3,5-Dichloro-7-ethylbenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.33(t,3H,J=7.7 Hz),
3.00(q,2H,J=7.7 Hz), 6.94(dd,1H,J=2.8,4.0 Hz), 7.01(dd,1H,J=2.0,3.6
Hz), 7.29(d,1H,J=2.0 Hz), 7.42(d,1H,J=1.6 Hz), 7.96(s,4H),
11.99(brs,1H)
Synthetic Example 180
4-{2-[5-(3-Fluoro-4,5,7-trimethylbenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.26(s,3H),
2.43(s,3H), 2.45(s,3H), 6.61-6.65(m,1H), 6.88-6.90(m,1H),
6.97-7.00(m,1H), 7.93(s,4H), 11.84(brs,1H).
Synthetic Example 181
4-{2-[5-(3-Chloro-4,5,7-trimethylbenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.27(s,3H),
2.50(s,3H), 2.57(s,3H), 6.89-6.92(m,1H), 6.94-6.97(m,1H),
6.98-7.00(m,1H), 7.94(s,4H), 11.85(brs,1H).
Synthetic Example 182
4-{2-[5-(3-Bromo-4,5,7-trimethylbenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.27(s,3H),
2.50(s,3H), 2.61(s,3H), 6.88-6.91(m,1H), 6.98-7.00(m,1H),
7.04-7.07(m,1H), 7.94(s,4H), 11.85(brs,1H).
Synthetic Example 183
4-{2-[5-(5-Fluoro-4-methylbenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.40(s,3H),
6.72-6.75(m,1H), 6.83-6.86(m,1H), 7.04(dd,1H,J=9.2,9.6 Hz),
7.29(s,1H), 7.39(dd,1H,J=3.6,8.4 Hz), 7.90(d,2H,J=8.4 Hz),
7.95(d,2H,J=8.4 Hz), 11.93(brs,1H).
Synthetic Example 184
4-{2-[5-(5-Chloro-4,7-dimethylbenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 3.24(s,3H),
3.39(s,3H), 6.73-6.75(m,6H), 6.84-6.86(m,1H), 7.12(s,1H),
7.27(s,1H), 7.88-7.90(d,2H,J=8.8 Hz), 7.94-7.96(d,2H,J=8.8 Hz),
11.59(brs,1H).
Synthetic Example 185
4-{2-[5-(5Chloro-3-fluoro-4,7-dimethylbenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.49(s,3H),
2.54(s,3H), 6.68-6.69(m,1H), 6.91-6.92(m,1H), 7.26(s,1H),
7.94(s,4H), 17.59(brs,1H).
Synthetic Example 186
4-{2-[5-(3-Bromo-5-chloro-4,7dimethylbenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.53(s,3H),
2.73(s,3H), 6.91-6.92(m,1H), 7.10-7.11(m,1H), 7.27(s,1H),
7.95(s,4H), 11.59(brs,1H).
Synthetic Example 187
4-{2-[5-(5-Chloro-3,4,7-trimethylbenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.52(s,3H),
2.62(s,3H), 3.29(s,3H), 6.61-6.62(m,1H), 6.86-6.88(m,1H),
7.15(s,1H), 7.89-7.91(d,2H,J=8.8 Hz), 7.92-7.94(d,2H,J=8.8 Hz),
11.56(brs,1H).
Synthetic Example 188
4-{2-[5-(5-Chloro-4-methylbenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.48(s,3H),
6.75-6.76(m,1H), 6.84-6.86(m,1H), 7.12(d,1H,J=1.2 Hz), 7.17(s,1H),
7.54(d,1H,J=1.6 Hz), 7.88-7.96(m,4H), 11.90(s,1H),
12.80(brs,1H).
Synthetic Example 189
4-{2-[5-(7-Chloro-5-fluoro-4-propylbenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 0.94(t,3H,J=7.2 Hz),
1.66(q,2H,J=7.2 Hz), 2.78(t,2H,J=7.2 Hz), 6.74-6.77(m,1H),
6.82-6.85(m,1H), 7.29(d,1H,J=10.0 Hz), 7.41(s,1H), 7.87(d,2H,J=8.4
Hz), 7.95(d,2H,J=8.4 Hz), 11.91(brs,1H).
Synthetic Example 190
4-{2-[5-(5-Fluoro-6-methylbenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 2.31(s,3H),
6.68-6.72(m,1H), 6.82-6.85(m,1H), 7.15(s,1H), 7.40(d,1H,J=10.0 Hz),
7.47(d,1H,J=6.4 Hz), 7.88(d,2H,J=8.4 Hz), 7.94(d,2H,J=8.4 Hz),
11.90(brs,1H).
Synthetic Example 191
4-{2-[5-(5,7-Difluorobenzofuran-2-yl)pyrrolyl}]benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 6.78-6.81(m,1H),
6.85-6.88(m,1H), 7.18-7.25(m,1H), 7.29(d,1H,J=3.2 Hz),
7.37(dd,1H,J=2.4,8.4 Hz), 7.89(d,2H,J=8.4 Hz), 7.95(d,2H,J=8.8 Hz),
12.02(brs,1H).
Synthetic Example 192
4-{2-[5-(4-Ethyl-5-fluorobenzofuran-2-yl)pyrrolyl}]benzoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.25(t,3H,J=7.6 Hz),
2.80-2.88(m,2H), 6.72-6.75(m,1H), 6.83-6.86(m,1H), 7.00-7.06(m,1H),
7.33(s,1H), 7.38-7.42(m,1H), 7.89(d,2H,J=8.8 Hz), 7.95(d,2H,J=8.8
Hz), 11.91(brs,1H).
Synthetic Example 193
4-{2-[5-(5-Chloro-7-ehtyl-3-fluorobenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.32(t,3H,J=7.6 Hz),
2.69(q,2H,J=7.6 Hz), 6.69-6.72(m,1H), 6.90-6.93(m,1H),
7.26-7.28(m,1H), 7.54-7.57(m,1H), 7.90-7.96(m,4H),
11.95(brs,1H).
Synthetic Example 194
4-[2-{5-(5-Chloro-7-methylmethylenedioxymethylbenzofuran-2-yl)pyrrolyl}]ben
zoic acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 3.36(s,3H),
4.74(s,2H), 4.85(s,2H), 6.74-6 75(m,1H), 6.85-6.87(m,1H),
7.22(s,1H), 7.25(d,1H,J=2 Hz), 7.69(d,1H,J=2 Hz), 7.88(d,2H,J=8.4
Hz), 7.95(d,2H,J=8.4 Hz), 11.93(brs,1H).
Synthetic Example 195
4-[2-{5-(5-Chloro-7-nitrilebenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 6.87-6.88(m,1H),
6.92-6.93(m,1H), 7.26(s,1H), 7.64(s,1H), 7.89(d,2H,J=8.4 Hz),
7.92(s,1H), 8.00(d,2H,J=8.4 Hz), 12.09(brs,1H).
Synthetic Example 196
4-[2-{5-(7-Chloro-4-ethyl-5-fluorobenzofuran-2-yl)pyrrolyl}]benzoic
acid
The title compound was obtained in the same manner as in Synthetic
Example 1.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.22(t,3H,J=7.2 Hz),
2.81(q,2H,J=7.2 Hz), 6.76-6.79(m,1H), 6.86-6.89(m,1H),
7.30(d,1H,J=10.0 Hz), 7.42(s,1H), 7.90(d,2H,J=8.4 Hz),
7.96(d,2H,J=8.4 Hz), 11.96(s,1H), 12.84(brs,1H).
Synthetic Example 197
4-[2-{5-(3-Methoxymethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-
2-yl)pyrrolyl}]benzoic acid
(A)
3,4-Dihydroxymethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene
7 g of aluminum chloride was added by portions to 200 ml solution
of 50 g 2,5-dichloro-2,5-dimethylhexane in orthoxylene at 0.degree.
C. under stirring. After the mixture was stirred at the same
temperature for 15 minutes, it was poured into ice-cold water and
extracted with ethyl acetate. The organic layer was washed with
brine, dried over anhydrous magnesium sulfate and then evaporated
to give 60 g of
2,3,5,5,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalene as a brown
oil.
128 g of N-bromosuccinic acid and 300 mg of bisazoisobutyronitrile
were added to 300 ml solution of 60 g of the unpurified
2,3,5,5,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalene in carbon
tetrachloride, and the mixture was stirred under heating at
80.degree. C. for 2 hours. The reaction mixture was cooled to
0.degree. C., 300 ml hexane was added thereto, and then the mixture
was filtered through a glass filter. The filtrate was evaporated to
give 110 g of
3,4-dibromomethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene
as a brown oil.
50 g of sodium carbonate was added at room temperature to a mixed
solution of 400 ml water and 400 ml dioxane containing 10 g of the
unpurified
3,4-dibromomethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene,
and the mixture was heated under reflux for 11 hours. The dioxane
was removed, and then the residue was extracted with ethyl acetate.
The organic layer was washed with brine, dried over anhydrous
magnesium sulfate and then evaporated. The resulting residue was
subjected to silica gel column chromatography to give 1.6 g of the
title compound as a yellow oil.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 1.46(s,12H),
1.68(s,4H), 3.50(brs,2H), 4.64(br s,4H), 7.24(s,4H).
(B)
2,3-(Methoxy-methylenedimethyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyln
aphthalene
1.8 ml trimethyl o-formate and 20 mg D-10-camphor sulfonic acid
were added at room temperature to 40 ml solution of 2.1 g
3,4-dihydroxymethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene
in dichloromethane under stirring. The resulting mixture was
stirred for 17.5 hours at the same temperature. Further, 1.8 ml
trimethyl o-formate and 20 mg D-10-camphor sulfonic acid were added
thereto at room temperature, and then the resulting mixture was
stirred for 4 hours at the same temperature. Water was added to the
reaction mixture, and then it was extracted with ethyl acetate. The
organic layer was washed with brine and an aqueous saturated sodium
bicarbonate solution, dried over anhydrous magnesium sulfate and
then evaporated. The resulting residue was subjected to silica gel
column chromatography to give 1.95 g of the title compound as a
yellow oil.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 1.26(s,12H),
1.48(s,4H), 3.46(s,3H), 4.66(d, J=14 Hz, 2H), 5.04(d, J=14 Hz, 2H),
5.45(s,1H), 7.02(s,2H), 7.02(s,2H).
(C)
3-Hydroxymethoxy-2-methoxymethoxymethyl-5,6,7,8-tetrahydro-5,5,8,8-tetrame
thylnaphthalene
A 1.0 M solution (4.53 ml) of diisobutyl aluminum in hexane was
added dropwise to 20 ml solution of 657 mg
2,3-(methoxy-methylenedimethyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyln
aphthalene in dichloromethane at -78.degree. C. under stirring. The
temperature was raised to room temperature over 1 hour and the
mixture was further stirred for 1 hour at the same temperature. The
reaction mixture was poured into 30 ml of 2 N aqueous sodium
hydroxide and then extracted with ethyl acetate. The organic layer
was washed with brine, dried over anhydrous magnesium sulfate and
then evaporated. The resulting residue was subjected to silica gel
column chromatography to give 491 mg of the title compound as a
yellow oil.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 1.28(s,12H), 1.64(s4H),
3.42(s,3H), 4.65(d,J=6.4 Hz,2H), 4.67(s,2H), 4.72(s,2H),
7.26(s,1H), 7.33(s,1H).
(D)
3-methoxymethyl-2-methoxymethoxymethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramet
hylnaphthalene
2 ml solution of 491 mg
3-hydroxymethyl-2-methoxymethoxymethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramet
hyl0naphthalene in dimethylformamide was added to 8 ml suspension
of 87 mg sodium hydride in dimethylformamide at 0.degree. C. under
stirring. The reaction mixture was stirred at room temperature for
30 minutes, then 0.261 ml methyl iodide was added thereto at
0.degree. C., and the mixture was stirred at room temperature for
additional 3 hours. An aqueous saturated ammonium chloride solution
was added to the reaction mixture followed by extracting with ethyl
acetate. The organic layer was washed with brine and dried over
anhydrous magnesium sulfate. Then, the residue obtained under
reduced pressure was subjected to silica gel column chromatography
to give 294 mg of the title compound as a yellow oil.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 1.28(s,12H),
1.66(s,4H), 3.00(s,3H), 3.04(s,4H), 4.48(d,J=6.8 Hz,2H),
4.62(s,2H), 4.71(s,2H), 7.29(s,1H), 7.30(s,1H).
(E)
2-hydroxymethyl-3-methoxymethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaph
thalene
1.0 ml of 10% aqueous hydrogen chloride was added at room
temperature to 5 ml solution of 294 mg
3-methoxymethyl-2-methoxymethoxymethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramet
hylnaphthalene in methanol. After the mixture was heated under
reflux for 1 hour, methanol was distilled off. Ethyl acetate was
added to the residue, and the resulting mixture was washed with
brine. The organic layer was dried over anhydrous magnesium
sulfate, and then the residue obtained under reduced pressure was
subjected to silica gel column chromatography to give 290 mg of the
title compound as a yellow oil.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 1.28(s,12H),
1.68(s,4H), 3.44(s,3H), 4.52(s,2H), 4.60(s,2H), 7.23(s,1H),
7.31(s,1H).
(F)
3-methoxymethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carbal
dehyde
0.321 ml dimethyl sulfoxide was added to 5 ml solution of 0.198 ml
oxazalyl chloride in dichloromethane at -78.degree. C., and the
mixture was stirred at the same temperature for 5 minutes. 2 ml
solution of 290 mg
2-hydroxymethyl-3-methoxymethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaph
thalene in dichloromethane was added to the mixture at -78.degree.
C., and the mixture was further stirred at the same temperature for
40 minutes. After 0.946 ml triethylamine was added to the reaction
mixture at -78.degree. C., the temperature was raised to room
temperature over 45 minutes. After water was added thereto, the
reaction solution was extracted with ethyl acetate. The organic
layer was washed with brine and dried over anhydrous magnesium
sulfate. Then, the residue obtained under reduced pressure was
subjected to silica gel column chromatography to give 190 mg of the
title compound as a yellow oil.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 1.32(s,12H),
1.72(s,4H), 3.40(s,3H), 3.48(s,3H), 4.47(s,2H), 4.81(s,2H),
7.50(s,1H), 7.80(s,1H).
(G) methyl
4-{4-[2-(3-methoxymethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthaleny
l)]-4-oxo-1-butanoyl}benzoate
156 mg of methyl 4-acryloylbenzoate (WO97/34869), 101 mg of
3-benzyl-5-(2-hydroxyethyl)thiazolium chloride and 0.315 ml
triethylamine were added at room temperature to 6 ml solution of
190 mg
3-methoxymethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carbal
dehyde in dimethylformamide. The mixture was heated at 80.degree.
C. for 1 hour under stirring followed by adding water thereto and
extracting with ethyl acetate. The organic layer was washed with
brine and dried over anhydrous magnesium sulfate. Then, the residue
obtained under reduced pressure was subjected to silica gel column
chromatography to give 91 mg of the title compound as a yellow
oil.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 1.30(s,6H), 1.34(s,6H),
1.72(s,4H), 3.40-3.45(m,7H), 3.94(s,3H), 4.70(s,2H), 7.55(s,1H),
7.83(s,1H), 8.00(d,J=8.4 Hz,2H), 8.15(d, J=8.4 Hz, 2H).
(H) methyl
4-{2-[5-(3-methoxymethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene
-2-yl)pyrrolyl]}benzoate
183 mg of ammonium acetate was added at room temperature to 6 ml
solution of 107 mg methyl
4-{4-[2-(3-methoxymethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthaleny
l)]-4-oxo-1-butanoyl}benzoatein methanol. The mixture was heated
under reflux for 8 hours. After methanol was distilled off, water
was added thereto followed by the extraction with ethyl acetate.
The organic layer was washed with brine and dried over anhydrous
magnesium sulfate. Then, the residue obtained under reduced
pressure was purified by silica gel column chromatography to give
46 mg of the title compound as a yellow solid.
.sup.1 H-NMR (CDCl.sub.3, 400 MHz) .delta.; 1.32(s,12H),
1.72(s,4H), 3.54(s,3H), 3.92(s,3H), 4.50(s,2H), 6.53(dd,J=2.4,3.6
Hz,1H), 6.75(dd,J=3.6, 2.4 Hz,1H), 7.27(s,1H), 7.54(d,J=8.4 Hz,2H),
7.57(s,1H), 8.03(d,J=8.4 Hz,2H).
(I)
4-{2-[5-(3-methoxymethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene
-2-yl)pyrrolyl]}benzoic acid
0.5 ml of 5 N NaOH was added at room temperature to 4 ml solution
of 46 mg methyl
4-{2-[5-(3-methoxymethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene
-2-yl)pyrrolyl]}benzoate in methanol. After the mixture was heated
under reflux for 30 minutes,10 ml water and 1 ml of 10% aqueous HCl
were added thereto. The resulting crystals were filtered, washed
with water and hexane, and then dried to give 35 mg of the title
compound.
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.24(s,6H),
1.28(s,6H), 1.68(s,4H), 3.30(s,3H), 4.20(s,2H), 6.32-6.35(m,1H),
6.75-6.77(m,1H), 7.39(s,1H), 7.41(s,1H), 7.76(d,J=8.4 Hz,2H),
7.90(d,J=8.4 Hz,2H).
Synthetic Example 198
4-{2-[5-(5,6,7,8-Tetrahydro-3,5,5,8,8-pentamethylnaphthalene-2-yl)pyrrolyl]
}benzoic acid
3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydronaphthalene was synthesized
according to the synthetic method described above by use of
3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene-2-carbaldehyde
as an intermediate obtained by vilsmeier reaction (JP-A 9-71566;
Referential Example 3).
.sup.1 H-NMR (DMSO-d.sub.6, 400 MHz) .delta.; 1.24(s,6H),
1.26(s,6H), 1.63(s,4H), 2.30(s,3H), 6.20-6.22(m,1H),
6.72-6.74(m,1H), 7.19(s,1H), 7.29(s,1H), 7.78(d,J=8.0 Hz,2H),
7.89(d,J=8 Hz,2H).
In the utilities of the present invention described above,
preferably the disease is nephritis, idiopathic thrombocytopenic
purpura or autoimmune anemia, the nephritis is glomerulonephritis
or lupus nephritis, the disease is systematic erythematosus,
nephritis, idiopathic thrombocytopenic purpura or autoimmune
anemia, the disease is glomerulonephritis or lupus nephritis, and
the disease is lupus nephritis.
The retinoic acid receptor (RAR) agonist used for the utilities of
the present invention is preferably a retinoic acid receptor
subtype .alpha. (RAR.sup..alpha.) agonist.
* * * * *